Substitute thiophenes and uses therof

ABSTRACT

This invention relates to novel compounds having the structural formula (I) and to their pharmaceutical salts, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cancer.

FIELD OF THE INVENTION

The present invention relates to novel substituted thiophenes, theirpharmaceutical compositions and methods of use. In addition, the presentinvention relates to therapeutic methods for the treatment andprevention of cancers.

BACKGROUND OF THE INVENTION

Chemotherapy and radiation exposure are currently the major options forthe treatment of cancer, but the utility of both these approaches isseverely limited by adverse effects on normal tissue, and the frequentdevelopment of tumor cell resistance. It is therefore desirable toimprove the efficacy of such treatments in a way that does not increasethe toxicity associated with them. One way to achieve this is by the useof specific sensitizing agents such as those described herein.

An individual cell replicates by making an exact copy of itschromosomes, and then segregating these into separate cells. This cycleof DNA replication, chromosome separation and division is regulated bymechanisms within the cell that maintain the order of the steps andensure that each step is precisely carried out. Involved in theseprocesses are the cell cycle checkpoints (Hartwell et al., Science, Nov.3, 1989, 246(4930):629-34) where cells may arrest to ensure DNA repairmechanisms have time to operate prior to continuing through the cycleinto mitosis. There are two such checkpoints in the cell cycle—the G1/Scheckpoint that is regulated by p53 and the G2/M checkpoint that ismonitored by the Ser/Thr kinase checkpoint kinase 1 (CHK1).

The cell cycle arrest induced by these checkpoints is a mechanism bywhich cells can overcome the damage resulting from radio- orchemotherapy, their abrogation by novel agents should increase thesensitivity of tumor cells to DNA damaging therapies. Additionally, thetumor specific abrogation of the G1/S checkpoint by p53 mutations in themajority of tumors can be exploited to provide tumor selective agents.One approach to the design of chemosensitizers that abrogate the G2/Mcheckpoint is to develop inhibitors of the key G2/M regulatory kinaseCHK1, and this approach has been shown to work in a number of proof ofconcept studies. (Koniaras et al., Oncogene, 2001, 20:7453; Luo et al.,Neoplasia, 2001, 3:411; Busby et al., Cancer Res., 2000, 60:2108;Jackson et al., Cancer Res., 2000, 60:566).

SUMMARY OF THE INVENTION

Provided herein are novel compounds of structural formula (I) or apharmaceutically acceptable salt thereof:

wherein:

R¹ and R² are at each occurrence independently selected from H,optionally substituted C₁₋₆alkyl, or optionally substitutedheterocyclyl; with the proviso that R¹ and R² are not both H; or R¹ andR² and the N to which they are attached in combination form anoptionally substituted heterocyclyl;

R⁴ is selected from H, OH, optionally substituted carbocyclyl,optionally substituted heterocyclyl, or optionally substitutedC₁₋₆alkyl;

R⁵ is selected from H, optionally substituted carbocyclyl, or optionallysubstituted C₁₋₆alkyl.

The invention also encompasses stereoisomers, enantiomers, invivo-hydrolysable precursors and pharmaceutically-acceptable salts ofcompounds of formula I, pharmaceutical compositions and formulationscontaining them, methods of using them to treat diseases and conditionseither alone or in combination with other therapeutically-activecompounds or substances, processes and intermediates used to preparethem, uses of them as medicaments, uses of them in the manufacture ofmedicaments and uses of them for diagnostic and analytic purposes.

DETAILED DESCRIPTION OF THE INVENTION

Provided herein are novel compounds of structural formula (I) or apharmaceutically acceptable salt or an in vivo-hydrolysable precursorthereof:

wherein:

R¹ and R² are at each occurrence independently selected from H,optionally substituted C₁₋₆alkyl, or optionally substitutedheterocyclyl; with the proviso that R¹ and R² are not both H; or R¹ andR² and the N to which they are attached in combination form anoptionally substituted heterocyclyl;

R⁴ is selected from H, OH, optionally substituted carbocyclyl,optionally substituted heterocyclyl, or optionally substitutedC₁₋₆alkyl;

R⁵ is selected from H, optionally substituted carbocyclyl, or optionallysubstituted C₁₋₆alkyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R¹ is an optionally substituted heterocyclyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R¹ is an optionally substituted heterocyclyl wherein1, 2, or 3 substitutents is/are independently selected from halogen,nitro, amino, cyano, trifluoromethyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, hydroxy, alkylhydroxy, carbonyl, —CH(OH)CH₃,—CH₂NH-alkyl-OH, alkyl-(OH)CH₃, —CH₂-phenyl-(OCH₃)₂, —Oalkyl, —OCH₃,—Ophenyl, —OCOalkyl, —NHCHO, —Nalkyl, —N-(alkyl)-CHO, —NH—CO-amino,—N-(alkyl)-CO-amino, —NH—COalkyl, —N-(alkyl)-COalkyl, -carboxy,-amidino, —CO-amino, —CO-alkyl, —CO₂alkyl, mercapto, —Salkyl,—SCH₂furanyl, —SO(alkyl), —SO₂(alkyl), —SO₂-amino, -alkylsulfonylamino,phenyl, anisole, dimethoxyphenyl, trimethoxyphenyl, halophenyl,cycloalkyl, heterocyclyl, -alkyl-NH-cycloalkyl, -alkyl-NH-heterocyclyl,-alkyl-NH-alkyl-OH, —C(═O)OC(CH₃)₃, —N(CH₃)₂, —N(CH₂CH₃)₂,-alkyl-NH-alkyl-heterocyclyl, -alkyl-aryl, -methyl-phenyl,alkyl-polycyclyl, alkyl-amino, alkyl-hydroxy, —CH₂NH-alkyl-heterocyclyl,—CH₂NHCH2CH(CH₃)₂, vicinal —O(alkyl)O—, vicinal —OC(haloalkyl)O—,vicinal —CH₂O(alkyl)O—, vicinal —S(alkyl)S— and —O(alkyl)S—.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R¹ is an optionally substituted heterocyclyl wherein1, 2, or 3 substitutents is/are independently-selected from: —OH,C(═O)OC(CH₃)₃, NH₂, C₁₋₆alkyl, methoxybenzene, or dimethoxy benezene.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R¹ is a heterocyclyl wherein heterocyclyl is selectedfrom piperdinyl, pyridinyl, pyrrolidinyl, pyrazinyl, azepanyl,azetidinyl, azabicyclozinyl, furanyl, thienyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R² is H.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R⁴ is H.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R⁵ is H or an optionally substituted C₁₋₆alkyl.

One embodiment of the present invention provides compounds of formula a)or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R⁵ is H or an optionally substituted C₁₋₆alkyl wherein1, 2 or 3 substitutents is/are independently selected from: NH₂, NHCH₃,N(CH₂CH₃)₂, N(CH₃)₂, OCH₃, OH, —C₁₋₆alkyl, morpholino, piperidinyl,pyrrolodinyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R⁵ is H or an optionally substituted C₁₋₃alkyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein R⁵ is H or an optionally substituted C₁₋₃alkyl wherein1, 2 or 3 substitutents is/are independently selected from: NH₂, NHCH₃,N(CH₂CH₃)₂, N(CH₃)₂, OCH₃, OH, —C₁₋₆alkyl, morpholino, piperidinyl,pyrrolodinyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein

R¹ is an optionally substituted heterocyclyl;

R² is H;

R⁴ is H;

R⁵ is H or an optionally substituted C₁₋₆alkyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein:

R¹ is an optionally substituted heterocyclyl wherein the substitutent isselected from one or more of the following: —NH₂, C₁₋₆alkyl,—C(═O)OC(CH₃)₃,

R² is H;

R⁴ is H;

R⁵ is H or an optionally substituted C₁₋₆alkyl wherein the substitutentis selected from one or more of the following: —C₁₋₆alkyl,—N(C₁₋₃alkyl)₂.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein:

R¹ is an optionally substituted heterocyclyl wherein the substitutent isselected from one or more of the following: —NH₂, C₁₋₆alkyl,—C(═O)OC(CH₃)₃,

R² is H;

R⁴ is H;

R⁵ is H or an optionally substituted C₁₋₃alkyl wherein 1, 2 or 3substitutents is/are independently selected from: NH₂, NHCH₃,N(CH₂CH₃)₂, N(CH₃)₂, OCH₃, OH, —C₁₋₆alkyl, morpholino, piperidinyl,pyrrolodinyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein:

R¹ is a heterocyclyl;

R² is H;

R⁴ is H;

R⁵ is H or a C₁₋₆alkyl.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt or an in vivo-hydrolysableprecursor wherein:

R¹ is a 6-membered heterocyclyl containing at least one N in the ring;

R² is H;

R⁴ is H;

R⁵ is a C₁₋₃alkyl.

One embodiment of the present invention provides compounds of formula(I) selected from the following:

-   tert-butyl    3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;-   tert-butyl    3-{[(2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[(3R)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{4-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxymethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidinylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(2-aminoethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1-methylpiperidinyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylazepan-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxymethyl)phenyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylpiperidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[2-(dimethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[2-(diethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(piperidin-4-ylmethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyrrolidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(1-ethylpiperidin-3-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[(3S)-1-ethylazepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(3-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;-   tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)pyrrolidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-piperidin-3-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(1-benzylpiperidin-4-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   tert-butyl    3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-azetidin-3-yl-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(2S)-pyrrolidin-2-ylmethyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyridin-4-ylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperidin-1-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-1-azabicyclo[2.2.2]oct-3-yl-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(2-hydroxyethyl)-5-(4-hydroxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(trans-4-hydroxycyclohexyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(2-methoxyphenyl)-N-piperidinylthiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(tetrahydrofuran-2-ylmethyl)thiophene-3-carboxamide;-   tert-butyl(3R)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-3-ylmethyl)thiophene-3-carboxamide;-   tert-butyl    3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azetidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(3-methoxypropyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide;-   N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]urea;-   2-[(aminocarbonyl)amino]-N-(2-methoxyethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-{2-[(2-furylmethyl)thio]ethyl}-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide;-   N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{3-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinolin-3-yl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(1,3-benzodioxol-5-ylmethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(3-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(5-methyl-2-furyl)methyl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-N-(4-fluorobenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   tert-butyl    4-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-N-(2-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-phenoxyethyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-2-ylethyl)thiophene-3-carboxamide;-   tert-butyl    4-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-N-(4-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide;-   tert-butyl(3S)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxamide;-   tert-butyl(3R)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   N-[3-{[(3S)-3-aminoazepan-1-yl]carbonyl}-5-(4-methoxyphenyl)-2-thienyl]urea;-   5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;-   5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;-   5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{([(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   N-(2-aminoethyl)-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino)}thiophene-3-carboxamide;-   5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   5-(4-methoxyphenyl)-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   tert-butyl    3-{[(5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;-   5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;-   N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea;-   N-[3-[(3-aminopyrrolidin-1-yl)carbonyl]-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea;-   tert-butyl    4-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   tert-butyl    3-{[(5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;-   5-[4-(2-diethylamino-ethoxy)-phenyl]-2-(3-hydroxy-urea)-thiophene-3-carboxylic    acid-(S)-piperidin-3-ylamide;-   2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(2-hydroxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;-   2-[(aminocarbonyl)amino]-5-[2-(benzyloxy)phenyl]-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt thereof for use as amedicament.

One embodiment of the present invention provides compounds of formula(I) or a pharmaceutically acceptable salt thereof in the manufacture ofa medicament for the treatment or prophylaxis of disorders associatedwith cancer.

One embodiment of the present invention provides a method for thetreatment of cancer comprising administering to a human atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a method for thetreatment of breast cancer, colorectal cancer, ovarian cancer, lung (nonsmall cell) cancer, malignant brain tumors, sarcomas, melanoma andlymphoma by administering a compound of formula I or a pharmaceuticallyacceptable salt thereof.

One embodiment the of present invention provides a method of treatingcancer by administering to a human a compound of formula (I) or apharmaceutically acceptable salt thereof and an anti-tumor agent.

One embodiment of the present invention provides a method of treatingcancer by administering to a human a compound of formula (I) or apharmaceutically acceptable salt thereof and a DNA damaging agent.

One embodiment of the present invention provides a method for thetreatment of infections associated with cancer comprising administeringto a host in need of such treatment a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof.

One embodiment of the present invention provides a method for theprophylaxis treatment of infections associated with cancer comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

One embodiment of the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof together with at least one pharmaceuticallyacceptable carrier, diluent or excipent.

One embodiment of the present invention provides a process for thepreparation of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, which comprises:(a) the reaction of a 2-aminothiophene shown below as formula II

wherein the hydrogen at the 2-amino position is displaced to form anamide, shown as formula III below

wherein the methyl ester is converted to an amide utilizing the desiredamine in conjuntion with an aluminate organometallic complex, to givethe product shown as formula IV below:

wherein the amide is converted to various substituted secondary ureas bythe reaction with various isocyanantes to yield the product shown asformula V below:

One embodiment of the present invention provides the use of a compoundof formula (VI) below or a pharmaceutically acceptabl salt or an in vivohydrolysable precursor in the manufacture of a compound of formula (I).

The definitions set forth in this application are intended to clarifyterms used throughout this application. The term “herein” means theentire application.

As used in this application, the term “optionally substituted,” as usedherein, means that substitution is optional and therefore it is possiblefor the designated atom to be unsubstituted. In the event a substitutionis desired then such substitution means that any number of hydrogens onthe designated atom is replaced with a selection from the indicatedgroup, provided that the normal valency of the designated atom is notexceeded, and that the substitution results in a stable compound. Forexample when a substituent is keto (i.e., ═O), then 2 hydrogens on theatom are replaced. Examples of such substituents are as follows:halogen, nitro, amino, cyano, trifluoromethyl, C₁₋₆alkyl, alkenyl,alkynyl, haloalkyl, alkoxy, hydroxy, alkylhydroxy, carbonyl, —CH(OH)CH₃,—CH₂NH-alkyl-OH, alkyl-(OH)CH₃, —CH₂-phenyl-(OCH₃)₂, —Oalkyl, —OCH₃,—Ophenyl, —OCOalkyl, —NHCHO, —N-(alkyl)-CHO, —Nalkyl, —NH—CO-amino,—N-(alkyl)-CO-amino, —NH—COalkyl, —N-(alkyl)-COalkyl, -carboxy,-amidino, —CO-amino, —CO-alkyl, —CO₂alkyl, mercapto, —Salkyl,—SCH₂furanyl, —SO(alkyl), —SO₂(alkyl), —SO₂-amino, -alkylsulfonylamino,phenyl, anisole, dimethoxyphenyl, trimethoxyphenyl, halophenyl,cycloalkyl, heterocyclyl, -alkyl-NH-cycloalkyl, -alkyl-NH-heterocyclyl,-alkyl-NH-alkyl-OH, —C(═O)OC(CH₃)₃, —N(CH₃)₂, —N(CH₂CH₃)₂,-alkyl-NH-alkyl-heterocyclyl, -alkyl-aryl, -methyl-phenyl,alkyl-polycyclyl, alkyl-amino, alkyl-hydroxy, —CH₂NH-alkyl-heterocyclyl,—CH₂NHCH2CH(CH₃)₂.

If the selection is attached to a ring the substituents could also beselected from: vicinal —O(alkyl)O—, vicinal —OC(haloalkyl)O—, vicinal—CH₂O(alkyl)O—, vicinal —S(alkyl)S— and —O(alkyl)S—.

A variety of compounds in the present invention may exist in particulargeometric or stereoisomeric forms. The present invention takes intoaccount all such compounds, including cis- and trans isomers, R- andS-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemicmixtures thereof, and other mixtures thereof, as being covered withinthe scope of this invention. Additional asymmetric carbon atoms may bepresent in a substituent such as an alkyl group. All such isomers, aswell as mixtures thereof, are intended to be included in this invention.The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.When required, separation of the racemic material can be achieved bymethods known in the art. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure areintended, unless the specific stereochemistry or isomeric form isspecifically indicated.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” used alone or as a suffix orprefix, is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having from 1 to 12 carbon atomsor if a specified number of carbon atoms is provided then that specificnumber would be intended. For example “C₁₋₆alkyl” denotes alkyl having1, 2, 3, 4, 5 or 6 carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. As used herein, “C₁₋₃ alkyl”,whether a terminal substituent or an alkylene group linking twosubstituents, is understood to specifically include both branched andstraight-chain methyl, ethyl, and propyl.

As used herein “alkylhydroxy” represents an alkyl group straight chainor branched as defined above with the indicated number of carbon atomswith one or more hydroxy groups attached. One such example ofalkylhydroxy would be —CH₂OH.

As used herein, the term “carbocyclyl” is intended to include bothalicyclic and aromatic ring structures wherein the closed ring is madeof carbon atoms. These may include fused or bridged polycyclic systems.Carbocyclyls may have from 3 to 10 carbon atoms in their ring structure,and often have 3, 4, 5, and 6 carbons in the ring structure. Forexample, “C₃₋₆ carbocyclyl” denotes such groups as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclopenta-diene or phenyl.

As used herein, the term “cycloalkyl” is intended to include saturatedring groups, having the specified number of carbon atoms. These mayinclude fused or bridged polycyclic systems. Preferred cycloalkyls havefrom 3 to 10 carbon atoms in their ring structure, and more preferablyhave 3, 4, 5, and 6 carbons in the ring structure. For example, “C₃₋₆cycloalkyl” denotes such groups as cyclopropyl, cyclobutyl, cyclopentyl,or cyclohexyl.

As used herein, “alkenyl” or “alkenylene” is intended to include from 2to 12 hydrocarbon atoms of either a straight or branched configurationwith one or more carbon-carbon double bonds that may occur at any stablepoint along the chain. Examples of “C₃₋₆alkenyl” include, but are notlimited to, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl,3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl.

As used herein, “alkynyl” or “alkynylene” is intended to include from 2to 12 hydrocarbon chains of either a straight or branched configurationwith one or more carbon-carbon triple bonds that may occur at any stablepoint along the chain. Examples of alkynyl include but are not limitedto ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl.

As used herein, the term “alkylcycloalkyl” is intended to mean an alkylattached to the formula atom modified with a cycloalkyl. Examples ofalkylcycloalkyl include, but are not limited to cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclopropylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl,cyclopropylpropyl, cyclopentylpropyl, cyclohexylpropyl,cycloheptylpropyl.

As used herein, “cycloalkenyl” refers to ring-containing hydrocarbylgroups having at least one carbon-carbon double bond in the ring, andhaving from 3 to 12 carbons atoms.

As used herein, “cycloalkynyl” refers to ring-containing hydrocarbylgroups having at least one carbon-carbon triple bond in the ring, andhaving from 7 to 12 carbons atoms.

As used herein, the term “aralkyl” refers to an alkyl group substitutedwith an aryl group (an aromatic or heteroaromatic group).

As used herein, “aromatic” refers to hydrocarbyl groups having one ormore polyunsaturated carbon rings having aromatic character, (e.g., 4n+2delocalized electrons) and comprising up to about 14 carbon atoms.

The term “aryl” as used herein includes 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, furan, imidazole, isoxazole,nicotinic, isonictinic, oxazole, phenyl, pyrazole, pyrazine, pyridazine,pyridine, pyrimidine, thiazole, thiophene, triazole and the like. Thosearyl groups having heteroatoms in the ring structure may also bereferred to as “heteroaryl” or “heteroaromatics.” The aromatic ring canbe substituted at one or more ring positions with such substituents asdescribed above. The term “aryl” also includes polycyclic ring systemshaving two or more cyclic rings in which two or more carbons are commonto two adjoining rings (the rings are “fused rings”) wherein at leastone of the rings is aromatic, for example, the other cyclic rings can becycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstitutedbenzenes, respectively. For example, the names 1,2-dimethylbenzene andortho-dimethylbenzene are synonymous.

As used herein, the term “heterocyclyl” or “heterocyclic” or“heterocycle” refers to a ring-containing monovalent and divalentstructures having one or more heteroatoms, independently selected fromN, O and S, as part of the ring structure and comprising from 3 to 20atoms in the rings, more preferably 3- to 7-membered rings. Heterocyclicgroups may be saturated or unsaturated, containing one or more doublebonds, and heterocyclic groups may contain more than one ring as in thecase of polycyclic systems. The heterocyclic rings described herein maybe substituted on carbon or on a heteroatom atom if the resultingcompound is stable. If specifically noted, nitrogen in the heterocyclylmay optionally be quaternized. It is understood that when the totalnumber of S and O atoms in the heterocyclyl exceeds 1, then theseheteroatoms are not adjacent to one another.

Examples of heterocyclyls include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H, 6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azabicyclo, azetidine, azepane, aziridine, azocinyl,benzimidazolyl, benzodioxol, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benzotriazolyl,benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl,cinnolinyl, diazepane, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dioxolane, furyl, 2,3-dihydrofuran, 2,5-dihydrofuran,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, homopiperidinyl,imidazolidine, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxirane, oxazolidinylperimidinyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, piperidonyl, 4-piperidonyl, purinyl, pyranyl, pyrrolidinyl,pyrroline, pyrrolidine, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, N-oxide-pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, pyridine, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroquinoline, tetrahydroisoquinolinyl,thiophane, thiotetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiopheneyl, thiirane, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl.

The terms “polycyclyl” or “polycyclic group” refer to two or more rings(for example, cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/orheterocyclyls) in which two or more carbons are common to two adjoiningrings, for example, the rings are “fused rings.” Rings that are joinedthrough non-adjacent atoms are termed “bridged” rings. Each of the ringsof the polycycle can be substituted with such substituents as describedabove, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, carbonyl,carboxyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike. Examples of such bridged heterocyclyls include quinuclidine,diazabicyclo[2.2.1]heptane and 7-oxabicyclo[2.2.1]heptane, substitutedpiperazine.

As used herein, the term “amine” or “amino” refers to groups of thegeneral formula —NRR′, wherein R and R′ are each independentlyrepresented by but not limited to hydrogen, alkyl, cycloalkyl, alkenyl,aryl, heteroaryl, aralkyl, or heteroaralkyl. Example of the amino groupinclude, but are not limited to NH₂, methylamine, ethylamine,dimethylamine, diethylamine, propylamine, benzylamine and the like.

As used herein, the term “amido” is art-recognized as anamino-substituted carbonyl and includes a moiety that can be representedby the general formula:

wherein R and R′ are each independently represented by but not limitedto hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl,aralkyl, or heteroaralkyl, or R and R′ may form a ring.

As used herein, “alkoxy” or “alkyloxy” represents an alkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge. Examples of alkoxy include, but are not limited to,methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy,n-pentoxy, isopentoxy, cyclopropylmethoxy, allyloxy and propargyloxy.Similarly, “alkylthio” or “thioalkoxy” represent an alkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge.

As used herein, the term “acyl” refers to groups of the of the generalformula —C(═O)—R, wherein R is hydrogen, hydrocarbyl radical. Examplesof acyl groups include, but are not limited to acetyl, propionyl,benzoyl, phenyl acetyl.

As used herein, the term “carbonyl” is art recognized and includes suchmoieties as can be represented by the general formula:

wherein X is a bond or represents an oxygen or sulfur, and R representsa hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R″ or a pharmaceuticallyacceptable salt, R′ represents a hydrogen, an alkyl, an alkenyl or—(CH₂)_(m)—R″, where m is an integer less than or equal to ten, and R″is alkyl, cycloalkyl, alkenyl, aryl, or heteroaryl. Where X is an oxygenand R and R′ is not hydrogen, the formula represents an “ester”. Where Xis an oxygen, and R is as defined above, the moiety is referred toherein as a carboxyl group, and particularly when R′ is a hydrogen, theformula represents a “carboxylic acid.” Where X is oxygen, and R′ is ahydrogen, the formula represents a “formate.” In general, where theoxygen atom of the above formula is replaced by sulfur, the formularepresents a “thiolcarbonyl” group. Where X is a sulfur and R and R′ isnot hydrogen, the formula represents a “thiolester.” Where X is sulfurand R is hydrogen, the formula represents a “thiolcarboxylic acid.”Where X is sulfur and R′ is hydrogen, the formula represents a“thiolformate.” On the other hand, where X is a bond, and R is not ahydrogen, the above formula represents a “ketone” group. Where X is abond, and R is hydrogen, the above formula is represents an “aldehyde”group.

As used herein, the term “sulfonylamino” is art-recognized and refers toa moiety that can be represented by the general formula:

wherein R and R′ are each independently represented by but not limitedto hydrogen, alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, heterocyclyl,aralkyl, or heteroaralkyl.

As used herein, the term “sulfonyl” is art-recognized and refers to amoiety that can be represented by the general formula:

wherein R is represented by but not limited to hydrogen, alkyl,cycloalkyl, alkenyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.

As used herein, “halo” or “halogen” refers to fluoro, chloro, bromo, andiodo. “Counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate,tosylate, benezensulfonate, and the like.

As used herein, “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted with 1 or more halogen(for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples ofhaloalkyl include, but are not limited to, trifluoromethyl,trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, andheptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group asdefined above with the indicated number of carbon atoms attached throughan oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy,2,2,2-trifluoroethoxy, and the like. “Haloalkylthio” is intended to meana haloalkyl group as defined above with the indicated number of carbonatoms attached through a sulphur bridge.

As used herein, the phrase-protecting protecting group” means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones respectively. The field ofprotecting group chemistry has been reviewed (Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 3^(rd) ed.; Wiley: New York,1999).

As used herein, “pharmaceutically acceptable” is employed herein torefer to those compounds, materials, compositions, and/or dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, allergic response, or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, phosphoric, and the like; and the saltsprepared from organic acids such as lactic, maleic, citric, benzoic,methanesulfonic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare used.

As used herein, “in vivo hydrolysable ester” means an in vivohydroysable (or cleavable) ester of a compound of the formula (I) thatcontains a carboxy or a hydroxy group. For example amino acid esters,C₁₋₆ alkoxymethyl esters like methoxymethyl; C₁₋₆alkanoyloxymethylesters like pivaloyloxymethyl; C₃₋₈cycloalkoxycarbonyloxy C₁₋₆alkylesters like 1-cyclohexylcarbonyloxyethyl, acetoxymethoxy, orphosphoramidic cyclic esters.

As used herein “stable compound” and “stable structure” are meant toindicate a compound that is sufficiently robust to survive isolation toa useful degree of purity from a reaction mixture, and formulation intoan efficacious therapeutic agent.

The anticancer treatment defined herein may be applied as a sole therapyor may involve, in addition to the compound of the invention,conventional surgery or radiotherapy or chemotherapy. Such chemotherapymay include one or more of the following categories of anti-tumoragents:

(i) antiproliferative/antineoplastic/DNA damaging drugs and combinationsthereof, as used in medical oncology, such as alkylating agents (forexample cis-platin, carboplatin, cyclophosphamide, nitrogen mustard,melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites(for example antifolates such as fluoropyrimidines like 5-fluorouraciland tegafur, raltitrexed, methotrexate, cytosine arabinoside,hydroxyurea and gemcitabine); antitumour antibiotics (for exampleanthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin,epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin);antimitotic agents (for example vinca alkaloids like vincristine,vinblastine, vindesine and vinorelbine and taxoids like taxol andtaxotere); topoisomerase inhibitors (for example epipodophyllotoxinslike etoposide and teniposide, amsacrine, topotecan, irinotecan andcamptothecin) and cytodifferentiating agents (for example All-transretinoic acid, 13-cis retinoic acid and fenretinide);

(ii) cytostatic agents such as antioestrogens (for example tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptordown regulators (for example fulvestrant), antiandrogens (for examplebicalutamide, flutamide, nilutamide and cyproterone acetate), LHRHantagonists or LHRH agonists (for example goserelin, leuprorelin andbuserelin), progestogens (for example megestrol acetate), aromataseinhibitors (for example as anastrozole, letrozole, vorazole andexemestane) and inhibitors of 5α-reductase such as finasteride;

(iii) agents which inhibit cancer cell invasion (for examplemetalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogen activator receptor function);

(iv) inhibitors of growth factor function, for example such inhibitorsinclude growth factor antibodies, growth factor receptor antibodies (forexample the anti-erbb2 antibody trastuzumab [Herceptin™] and theanti-erbb1 antibody cetuximab [C225]), farnesyl transferase inhibitors,tyrosine kinase inhibitors and serine/threonine kinase inhibitors, forexample inhibitors of the epidermal growth factor family (for exampleEGFR family tyrosine kinase inhibitors such asN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(CI 1033)), for example inhibitors of the platelet-derived growth factorfamily and for example inhibitors of the hepatocyte growth factorfamily;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor, (for example the anti-vascularendothelial cell growth factor antibody bevacizumab [Avastin™],compounds such as those disclosed in published International PatentApplications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) andcompounds that work by other mechanisms (for example linomide,inhibitors of integrin αvβ3 function and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in International Patent Applications WO 99/02166, WO 00/40529,WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(vii) antisense therapies, for example those which are directed to thetargets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) gene therapy approaches, including for example approaches toreplace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2,GDEPT (gene-directed enzyme pro-drug therapy) approaches such as thoseusing cytosine deaminase, thymidine kinase or a bacterial nitroreductaseenzyme and approaches to increase patient tolerance to chemotherapy orradiotherapy such as multi-drug resistance gene therapy; and

(ix) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumour cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumour cell lines and approaches usinganti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention.

Compounds of the present invention may be administered orally,parenteral, buccal, vaginal, rectal, inhalation, insufflation,sublingually, intramuscularly, subcutaneously, topically, intranasally,intraperitoneally, intrathoracially, intravenously, epidurally,intrathecally, intracerebroventricularly and by injection into thejoints.

The dosage will depend on the route of administration, the severity ofthe disease, age and weight of the patient and other factors normallyconsidered by the attending physician, when determining the individualregimen and dosage level as the most appropriate for a particularpatient.

An effective amount of a compound of the present invention for use intherapy of infection is an amount sufficient to symptomatically relievein a warm-blooded animal, particularly a human the symptoms ofinfection, to slow the progression of infection, or to reduce inpatients with symptoms of infection the risk of getting worse.

For preparing pharmaceutical compositions from the compounds of thisinvention, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets, and suppositories.

A solid carrier can be one or more substances, which may also act asdiluents, flavoring agents, solubilizers, lubricants, suspending agents,binders, or tablet disintegrating agents; it can also be anencapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

For preparing suppository compositions, a low-melting wax such as amixture of fatty acid glycerides and cocoa butter is first melted andthe active ingredient is dispersed therein by, for example, stirring.The molten homogeneous mixture is then poured into convenient sizedmolds and allowed to cool and solidify.

Suitable carriers include magnesium carbonate, magnesium stearate, talc,lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose,sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and thelike.

Some of the compounds of the present invention are capable of formingsalts with various inorganic and organic acids and bases and such saltsare also within the scope of this invention. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, phosphoric, and the like; and the salts preparedfrom organic acids such as lactic, maleic, citric, benzoic,methanesulfonic, trifluoroacetate and the like.

In one embodiment a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment (includingprophylactic treatment) of mammals including humans, it is normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition.

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain, or beco-administered (simultaneously or sequentially) with, one or morepharmacological agents of value in treating one or more diseaseconditions referred to herein.

The term composition is intended to include the formulation of theactive component or a pharmaceutically acceptable salt with apharmaceutically acceptable carrier. For example this invention may beformulated by means known in the art into the form of, for example,tablets, capsules, aqueous or oily solutions, suspensions, emulsions,creams, ointments, gels, nasal sprays, suppositories, finely dividedpowders or aerosols or nebulisers for inhalation, and for parenteral use(including intravenous, intramuscular or infusion) sterile aqueous oroily solutions or suspensions or sterile emulsions.

Liquid form compositions include solutions, suspensions, and emulsions.Sterile water or water-propylene glycol solutions of the activecompounds may be mentioned as an example of liquid preparations suitablefor parenteral administration. Liquid compositions can also beformulated in solution in aqueous polyethylene glycol solution. Aqueoussolutions for oral administration can be prepared by dissolving theactive component in water and adding suitable colorants, flavoringagents, stabilizers, and thickening agents as desired. Aqueoussuspensions for oral use can be made by dispersing the finely dividedactive component in water together with a viscous material such asnatural synthetic gums, resins, methyl cellulose, sodium carboxymethylcellulose, and other suspending agents known to the pharmaceuticalformulation art.

The pharmaceutical compositions can be in unit dosage form. In suchform, the composition is divided into unit doses containing appropriatequantities of the active component. The unit dosage form can be apackaged preparation, the package containing discrete quantities of thepreparations, for example, packeted tablets, capsules, and powders invials or ampoules. The unit dosage form can also be a capsule, cachet,or tablet itself, or it can be the appropriate number of any of thesepackaged forms.

Compounds of formula (I) have been shown to inhibit checkpoint kinaseactivity in vitro. Inhibitors of checkpoint kinase have been shown toallow cells to progress inappropriately to the metaphase of mitosisleading to apoptosis of effected cells, and to therefore haveanti-proliferative effects. Therefore it is believed that the compoundsof formula (I) may be used for the treatment of neoplastic disease.Hence compounds of formula (I) and their salts are expected to be activeagainst neoplastic disease such as carcinoma of the brain, breast,ovary, lung, colon, prostate, skin or other tissues, as well asleukemias and lymphomas, tumors of the central and peripheral nervoussystem, and other tumor types such as melanoma, sarcomas, fibrosarcomaand osteosarcoma. In addition, compounds of formula (I) are alsoexpected to be useful for the treatment other proliferative diseases. Itis expected that the compounds of formula (I) would most likely be usedin combination with a broad range of DNA damaging agents but could alsobe used as a single agent.

Generally, the compounds of formula (I) have been identified in one orboth assays described below as having an IC₅₀ value of 100 micromolar orless. For example compound of example 2 has an IC₅₀ value of 10 nM.

Checkpoint Kinase 1 Assay: This in vitro assay measures the inhibitionof CHK1 kinase by compounds. The kinase domain is expressed inbaculovirus and purified by the GST tag. Purified protein andbiotinylated peptide substrate (Cdc25C) is then used in a 384 wellautomated Scintillation Proximity Assay (SPA). Specifically, peptide,enzyme and reaction buffer are mixed and aliquoted into a 384 well platecontaining dilution series of compounds and controls. Cold and hot ATPare then added to initiate the reaction. After 2 hours, a SPA beadslurry, CsCl2 and EDTA are added to stop the reaction and capture thebiotinylated peptide. Plates are then counted on a Topcount. Data isanalyzed and IC50s determined for individual compounds.

Abrogation Assay: This cellular assay measures the ability of CHK1inhibitors to abrogate the DNA-damage induced G2/M checkpoint. Compoundsactive against the enzyme (<2 uM) are tested in the cellular assay.Briefly HT29 cells (colon cancer cell line, p53 null) are plated in 96well plates on day 1. The following day, cells are treated withcamptothecin for 2 hours to induce DNA damage. After 2 hours,camptothecin is removed and cells are treated for an additional 18 hourswith test compound and nocodazole, a spindle poison that traps in cellsin mitosis that abrogate the checkpoint. Cells are then fixed withformaldehyde, stained for the presence of phosphohistone H3, a specificmarker for mitosis and labeled with Hoechst dye so that cell number canbe measured. Plates are scanned using the Mitotic Index protocol on theArray Scan (Cellomics). As a positive control for abrogation, 4 mMcaffeine is used. Compounds are tested in a 12-point dose response intriplicate. Data is analyzed and EC50s determined for individualcompounds.

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Such methods include, but are not limited to,those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described herein. The reactions are performedin solvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents, which are notcompatible with the reaction conditions, will be readily apparent to oneskilled in the art and alternate methods must then be used.

The starting materials for the examples contained herein are eithercommercially available or are readily prepared by standard methods fromknown materials. For example the following reactions are illustrationsbut not limitations of the preparation of some of the starting materialsand examples used herein.

General procedures for making the compounds of the invention is asfollows:

The first of these procedures initiates from a common intermediate. Thisintermediate 2-aminothiophene core is produced by a one-pot Gewaldsynthesis from reaction of cyanomethylacetate with various benzaldehydesand elemental sulfur under basic conditions shown below in Scheme I.

If not commercially available, the corresponding benzaldehydes could besynthesized using some or all of the transformations described in SchemeII.

Compounds of Formula (I) can then be synthesized from the generalsynthetic methods described below in Schemes III-IX. The first generalmethod shown in Scheme III involves a Weinreb amide formation fromreaction of either the trichloroacetyl-protected or free urea with anamino aluminate organometallic complex.

An alternate method for the generation of similar compounds is describedin Scheme IV. This general route utilizes the same starting2-aminothiophene ester from Scheme III but amide bond formation isexecuted from the reaction of the corresponding carboxylic acids withvarious amines. A variety of coupling agents can be used to effect thistransformation including EDCI, DIC, BOP, and HATU under standardcoupling methods very familiar to those practicing and trained in theart of organic synthesis. Generation of the final primary urea is thenperformed using a simple two-step reaction withtrichloroacetylisocyanate followed by cleavage with ammonia in methanol.

As shown in the following Schemes V-VII, the amide product formed priorto urea generation in Scheme IV can be used as a common intermediate forthe formation of various substituted ureas where R⁴ is not hydrogen.Reaction with isocyanantes, acyl azides (in particular pyrazine acylazides), or carbonyldiimidazole and amines (in particular hydroxylaminehydrochloride), leads to the creation of various substituted secondaryureas where R⁴ is selected from OH, optionally substituted carbocyclyl,optionally substituted heterocyclyl, or optionally substitutedC₁₋₆alkyl.

An additional general process presented in this invention involves animprovement on the construction of general compounds with formula (I).The method, which employs a Suzuki Coupling of a 5-bromothiopheneintermediate as its key transformation, is shown in Scheme VIII. Thismethod allows for increased diversity much later in the synthesis and isamenable to parallel combinatorial methods of organic synthesis.Commercially available 2-amino-thiophene-3-carboxylic acid methyl esteris protected as the trichloroacetyl urea, followed by selectivebromination at the 5-position with bromine in acetic acid. Removal ofthe protecting group with ammonia in methanol, followed by Weinrebamidation yields the common intermediate. Standard Suzuki reactionconditions are then employed to finally generate the target compounds.

If the final compound generated from any of the above-mentioned methodsor schemes has a protecting group on nitrogen (in particular acarbamate) or oxygen (in particular an ether or ester) present anywhereon the molecule standard methods of removal can be utilized to generatefinal compounds. Shown in Scheme IX is the general method used for thedeprotection of a tert-butoxycarbonyl carbamate to yield the secondaryamine product (R²═XNHR³) as the corresponding hydrochloride ortrifluoroacetate salt. Cleavage of methyl ethers to phenols (not shown)is affected by reaction with boron tribromide in methylene chloride.Both of these methods are very familiar with those trained in the art oforganic synthesis.

EXAMPLES

TABLE 1 LCMS (M+1, Synthesis ES or APCI ¹H NMR (d₆-DMSO Method IUPACName Ex. detection) unless stated otherwise) (Scheme) tert-butyl 3-{[(2-1 560 MeOD; 7.55(d, 2H), 7.45(s, 1H), III[(aminocarbonyl)amino]-5-{4-[2- 7.05(d, 2H), 4.35(m, 2H),(diethylamino)ethoxy]phenyl}-3- 3.90(m, 3H), 3.60(m, 2H),thienyl)carbonyl]amino}piperidine-1- 3.30(m, 4H), 2.95(dd, 2H),carboxylate trifluoroacetate 2.10(m, 1H), 1.80(m, 1H), 1.50(m, 2H),1.40(s, 9H), 1.35(t, 6H) 2-[(aminocarbonyl)amino]-5-{4-[2- 2 460 III(diethylamino)ethoxy]phenyl}-N- piperidin-3-ylthiophene-3-carboxamidetrifluoroacetate 2-[(aminocarbonyl)amino]-5-{3-[2- 3 460 III(diethylamino)ethoxy]phenyl}-N- piperidin-3-ylthiophene-3-carboxamidetrifluoroacetate 2-[(aminocarbonyl)amino]-5-(4- 4 375 1.76-1.49(m, 2H),1.93(brs, III methoxyphenyl)-N-[(3S)-piperidin-3- 2H), 2.85(t, 2H),3.16(s, 1H), yl]thiophene-3-carboxamide 3.22(brd, 1H), 3.31(brd, 1H),3.77(s, 3H), 4.11(brs, 1H), 6.97(d, 2H, J=8.59Hz), 7.45(d, 2H,J-8.59Hz), 7.58(s, 1H), 8.02(d, 1H), J=7.33Hz), 8.65(brs, 2H), 10.81(s,1H) tert-butyl 3-{[(2- 5 560 MeOD; 7.65(d, 1H), 7.30(dd, III[(aminocarbonyl)amino]-5-{3-[2- 2H), 7.20(s, 1H), 6.90(d, 1H),(diethylamino)ethoxy]phenyl}-3- 4.35(m, 2H), 3.90(m, 2H),thienyl)carbonyl]amino}piperidine-1- 3.60(m, 2H), 3.30(m, 4H),carboxylate trifluoroacetate 3.00(m, 2H), 2.10(m, 1H), 1.80(m, 1H),1.50(m, 2H), 1.45(s, 9H), 1.40(t, 6H) 2-[(aminocarbonyl)amino]-5-{4-[2-6 460 MeOD; 7.52(d, 2H), 7.49(s, 1H), III(diethylamino)ethoxy]phenyl}-N- 7.01(d, 2H), 4.35(m, 2H),piperidin-4-ylthiophene-3-carboxamide 3.60(m, 2H), 3.48(m, 1H), 3.42(m,2H), 3.33(q, 4H), 3.13(m, 2H), 2.14(m, 2H), 1.85(m, 2H), 1.35(t, 6H)2-[(aminocarbonyl)amino]-N-[(3R)- 7 389 CDCl3; 11.30(br s, 1H), IIIazepan-3-yl]-5-(4- 7.50(d, 2H), 7.05(d, 1H), 7.00(s,methoxyphenyl)thiophene-3- 1H), 6.85(d, 2H), 5.15(s, 2H), carboxamide4.20(m, 1H), 3.80(s, 3H), 3.10(m, 1H), 3.00(m, 2H), 2.80(m, 1H), 1.80(m,2H), 1.70(m, 3H), 1.50(m, 1H) N-(3-[(4-aminopiperidin-1-yl)carbonyl]- 8460 MeOD; 7.43(d, 2H), 6.93(d, III 5-{4-[2-(diethylamino)ethoxy]phenyl}-2H), 6.92(s, 1H), 4.33(m, 2H), 2-thienyl)urea trifluoroacetate 4.27(dd,2H), 3.52(dd, 2H), 3.32(m, 1H), 3.24(q, 4H), 3.02(m, 2H), 1.99(m, 1H),1.95(m, 1H), 1.47(m, 2H), 1.27(t, 6H) 2-[(aminocarbonyl)amino]-5-{4-[2-9 483 MeOD; 7.61(m, 1H), 7.57(s, III (diethylamino)ethoxy]phenyl}-N-[3-1H), 7.49(m, 1H), 7.47(d, 2H), (hydroxymethyl)phenyl]thiophene-3-7.23(t, 1H), 7.03(dd, 1H), carboxamide trifluoroacetate (salt) 6.93(d,2H), 4.52(s, 2H), 4.27(dd, 2H), 4.31(dd, 2H), 3.24(q, 4H), 1.27(t, 6H)2-[(aminocarbonyl)amino]-5-{3-[2- 10 460 MeOD; 7.62(s, 1H), 7.29(dd, III(diethylamino)ethoxy]phenyl}-N- 1H), 7.24(m, 1H), 7.13(m, 1H),piperidin-4-ylthiophene-3-carboxamide 6.87(m, 1H), 4.35(dd, 2H),trifluoroacetate 3.59(dd, 2H), 3.46(m, 1H), 3.40(m, 2H), 3.31(q, 4H),3.10(m, 2H), 2.16(m, 2H), 1.83(m, 2H), 1.34(t, 6H)2-[(aminocarbonyl)amino]-N-(2- 11 335 MeOD; 7.38(d, 2H), 7.36(s, 1H),III aminoethyl)-5-(4- 6.82(d, 2H), 3.70(s, 3H),methoxyphenyl)thiophene-3- 3.57(dd, 2H), 3.10(dd, 2H), carboxamide2-[(aminocarbonyl)amino]-5-(4- 12 375 1.70(m, 2H), 1.99(d, 2H, IIImethoxyphenyl)-N-piperidin-4- J=12.88Hz), 3.01(q, 2H,ylthiophene-3-carboxamide J=11.03Hz), 3.35(d, 2H, J=12.38Hz), 3.76(s,3H), 4.01(brs, 1H), 6.97(d, 2H, J=8.59Hz), 7.45(d, 2H, J=8.84Hz),7.63(s, 1H), 8.04(d, 1H, J=7.07Hz), 8.43(d, 1H, J=9.10Hz), 8.65(d, 1H,J=8.59Hz), 10.91(s, 1H) 2-[(aminocarbonyl)amino]-5-{3-[2- 13 454 MeOD;9.51(s, 1H), 8.75(d, 1H), III (diethylamino)ethoxy]phenyl}-N- 8.51(m,1H), 7.97(s, 1H), pyridin-3-ylthiophene-3-carboxamide 7.93(m, 1H),7.35(t, 1H), trifluoroacetate 7.29(m, 2H), 6.93(m, 1H), 4.45(dd, 2H),3.67(dd, 2H), 3.39(q, 4H), 1.42(t, 6H) 2-[(aminocarbonyl)amino]-5-(4- 14389 1.76(q, 2H), 2.04(d, 2H, III methoxyphenyl)-N-(1-methylpiperidin-J=12.38Hz), 2.77(brd, 3H), 4-yl)thiophene-3-carboxamide 3.08(q, 2H),3.48(d, 2H, J=11.62Hz), 3.76(s, 3H), 3.96(m, 1H), 6.97(d, 2H), 7.45(d,2H, J=8.84Hz), 7.63(s, 1H), 8.07(d, 1H, J=7.33Hz), 9.62(brs, 1H),10.91(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 15 403 CDCl3; 11.35(br s,1H), III methoxyphenyl)-N-[(3S)-1- 7.50(d, 2H), 7.15(d, 1H), 6.95(s,methylazepan-3-yl]thiophene-3- 1H), 6.90(d, 2H), 5.30(s, 2H),carboxamide hydrochloride 4.20(m, 1H), 3.80(s, 3H), 2.85(m, 1H), 2.80(d,1H), 2.60(dd, 1H), 2.40(m, 1H), 2.45(s, 3H), 1.50-2.00(m, 6H)2-[(aminocarbonyl)amino]-5-{3-[2- 16 483 MeOD; 7.84(s, 1H), 7.75(m, III(diethylamino)ethoxy]phenyl}-N-[3- 1H), 7.63(dd, 1H), 7.35(t, 2H),(hydroxymethyl)phenyl]thiophene-3- 7.32(m, 1H), 7.22(m, 1H), carboxamidetrifluoroacetate (salt) 7.16(dd, 1H), 6.92(m, 1H), 4.65(s, 2H), 4.41(dd,2H), 3.63(dd, 2H), 3.37(q, 4H), 1.40(t, 6H)2-[(aminocarbonyl)amino]-5-{4-[2- 17 446 MeOD; 7.46(d, 2H), 7.16(s, 1H),III (diethylamino)ethoxy]phenyl}-N- 6.95(d, 2H), 4.28(dd, 2H),pyrrolidin-3-ylthiophene-3- 3.89(m, 3H), 3.70(m, 2H), carboxamidetrifluoroacetate 3.53(dd, 2H), 3.28(q, 4H), 2.30(m, 1H), 2.06(m, 1H),1.29(t, 6H) 2-[(aminocarbonyl)amino]-5-{4-[2- 18 454 MeOD; 9.59(s, 1H),8.75(d, 1H), III (diethylamino)ethoxy]phenyl}-N- 8.56(d, 1H), 8.00(m,2H), pyridin-3-ylthiophene-3-carboxamide 7.71(s, 1H), 7.59(d, 2H),7.07(d, trifluoroacetate 2H), 4.41(dd, 2H), 3.65(dd, 2H), 3.38(q, 4H),1.40(t, 6H) 2-[(aminocarbonyl)amino]-5-(4- 19 389 CDCl3; 11.25(br s,1H), III methoxyphenyl)-N-[(3S)-1- 7.50(d, 2H), 7.15(s, 1H), 6.85(d,methylpiperidin-3-yl]thiophene-3- 2H), 6.90(m, 2H), 5.40(s, 2H),carboxamide hydrochloride 4.25(m, 1H), 3.80(s, 3H), 2.40-2.80(m, 4H),2.30(s, 3H), 2.20(m, 1H), 1.50-1.90(m, 3H)2-[(aminocarbonyl)amino]-5-{3-[2- 20 446 MeOD; 7.40(s, 1H), 7.35(dd, III(diethylamino)ethoxy]phenyl}-N- 1H), 7.27(dd, 1H), 7.20(s, 1H),pyrrolidin-3-ylthiophene-3- 6.93(m, 1H), 4.42(dd, 2H), carboxamidetrifluoroacetate 4.01(m, 3H), 3.83(m, 2H), 3.65(dd, 2H), 3.37(q, 4H),2.44(m, 1H), 2.18(m, 1H), 1.40(t, 6H) 2-[(aminocarbonyl)amino]-5-(4- 21389 1.22(dd, 1H, J1=12.38Hz, III methoxyphenyl)-N-[(3R)-piperidin-3-J2=2.53Hz), 1.57(d, 1H, ylmethyl]thiophene-3-carboxamide J=13.14Hz),1.78(brt, 2H), 1.95(brs, 1H), 2.60(q, 1H, J=11.37), 2.78(q, 1H,J=10.61Hz), 3.09(m, 1H), 3.25(m, 3H), 3.77(s, 3H), 6.97(d, 2H,J=8.59Hz), 7.44(d, 2H, J=8.84Hz), 7.58(s, 1H), 8.24(brs, 1H), 8.30(brt,1H), 8.57(brs, 1H), 10.92(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 22 361III methoxyphenyl)-N-[(3S)-pyrrolidin-3- yl]thiophene-3-carboxamide2-[(aminocarbonyl)amino]-5-(4- 23 361 IIImethoxyphenyl)-N-[(3R)-pyrrolidin-3- yl]thiophene-3-carboxamide2-[(aminocarbonyl)amino]-N-[2- 24 363 MeOD; 7.37(d, 2H), 7.35(s, 1H),III (dimethylamino)ethyl]-5-(4- 6.80(d, 2H), 3.69(s, 3H),methoxyphenyl)thiophene-3- 3.64(m, 2H), 3.29(m, 2H), carboxamide 2.91(s,6H) 2-[(aminocarbonyl)amino]-N-[2- 25 391 III (diethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3- carboxamide 2-[(aminocarbonyl)amino]-N-[(3S)-26 389 δ 10.9, s, 1H; δ 9.58, br s, 1H; III azepan-3-yl]-5-(4- δ 9.29,br s, 1H; δ 8.39, d, 1H; methoxyphenyl)thiophene-3- δ 7.82, s, 1H; δ7.48, d, 2H; carboxamide hydrochloride δ 6.96, d, 2H; δ 4.36, m, 1H; δ3.77, s, 3H; δ 3.29, m, 1H; δ 3.20, m, 2H; δ 3.07, m, 1H; δ 1.98, m, 1H;δ 1.84, m, 4H; δ 1.59, m, 1H 2-[(aminocarbonyl)amino]-5-(4- 27 3751.52(m, 2H), 1.76(brs, 1H), III methoxyphenyl)-N-[(3R)-piperidin-3-1.89(brs, 1H), 2.61(m, 2H), yl]thiophene-3-carboxamide 2.99(t, 1H),3.16(m, 1H), 3.76(s, 3H), 3.95(brs, 1H), 6.97(d, 2H), 7.46(d, 2H),7.61(s, 1H), 7.89(d, 1H), 10.90(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 28389 1.06(m, 2H), 1.62(d, 3H, III methoxyphenyl)-N-(piperidin-4-J=10.11Hz), 2.95(d, 2H, ylmethyl)thiophene-3-carboxamide J=12.13Hz),3.11(t, 2H, J=5.68Hz), 3.76(s, 3H), 6.90(d, 1H, J=8.59Hz), 6.96(d, 2H,J=8.59Hz), 7.44(d, 2H, J=8.59Hz), 7.61(s, 1H), 8.14(t, 1H, J=5.43Hz),10.99(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 29 361 2.02(brt, 2H,J=5.81Hz), III methoxyphenyl)-N-pyrrolidin-3- 2.22(dd, 2H, J1=13.52Hz,J2=6.69Hz), ylthiophene-3-carboxamide 3.21(dd, 1H, J1=13.77Hz,J2=6.95Hz), 3.68(brs, 1H), 3.76(s, 3H), 3.86(brs, 1H), 6.96(brm, 2H),7.28(brs, 1H), 7.50(d, 2H, J=8.84Hz), 8.16(brs, 1H), 10.31(s, 1H)2-[(aminocarbonyl)amino]-N-(1- 30 403 11.0(s, 1H), 7.80(d, 1H), 7.65(s,III ethylpiperidin-3-yl)-5-(4- 1H), 7.45(d, 2H), 6.95(d, 2H),methoxyphenyl)thiophene-3- 6.90(br s, 2H), 3.90(m, 1H), carboxamidehydrochloride 3.75(s, 3H), 2.85(dd, 2H), 2.30(m, 2H), 1.80(m, 3H),1.70(m, 1H), 1.50(m, 1H), 13.0(m, 1H), 1.0(t, 3H)2-[(aminocarbonyl)amino]-N-[(3S)-1- 31 417 11.0(s, 1H), 7.75(d, 1H),7.65(s, III ethylazepan-3-yl]-5-(4- 1H), 7.45(d, 2H), 6.95(d, 2H),methoxyphenyl)thiophene-3- 6.90(br s, 2H), 4.05(m, 1H), carboxamidehydrochloride 3.75(s, 3H), 2.75(m, 1H), 2.40-2.70(m, 5H), 1.85(m, 1H),1.40-1.75(m, 5H), 0.95(t, 3H) 2-[(aminocarbonyl)amino]-5-(3- 32 361 IIIhydroxyphenyl)-N-piperidin-4- ylthiophene-3-carboxamide2-[(aminocarbonyl)amino]-5-(4- 33 361 III hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide 2-[(aminocarbonyl)amino]-5-(3- 34 375 IIImethoxyphenyl)-N-piperidin-4- ylthiophene-3-carboxamide tert-butyl(3S)-3-({[2- 35 481 III [(aminocarbonyl)amino]-5-(4- methoxyphenyl)-3-thienyl]carbonyl}amino)pyrrolidine-1- carboxylate2-[(aminocarbonyl)amino]-5-(4- 36 375 III methoxyphenyl)-N-piperidin-3-ylthiophene-3-carboxamide 2-[(aminocarbonyl)amino]-N-(1- 37 465 1.75(m,2H), 2.08(d, 2H, III benzylpiperidin-4-yl)-5-(4- J=13.39Hz), 3.10(m,2H), methoxyphenyl)thiophene-3- 3.43(d, 2H, J=11.62Hz), 3.76(s,carboxamide 3H), 3.95(m, 1H), 4.31(d, 2H, J=4.55Hz), 6.97(d, 2H,J=8.59Hz), 7.45(d, 2H, J=8.59Hz), 7.49(brs, 5H, J=2.27Hz), 7.61(s, 1H),8.05(d, 1H, J=6.82Hz), 9.65(brs, 1H), 10.89(s, 1H) tert-butyl 3-({[2- 38475 1.39(s, 9H), 1.46-1.97(bm, III [(aminocarbonyl)amino]-5-(4- 4H),2.72(t, 2H), 3.16(s, 2H), methoxyphenyl)-3- 3.77(s, 3H), 6.96(d, 2H),thienyl]carbonyl}amino)piperidine-1- 7.45(d, 2H), 7.62(s, 1H), 7.85(brs,carboxylate 1H), 8.77(d, 1H), 10.95(s, 1H)2-[(aminocarbonyl)amino]-5-[4-(2- 39 494 IIIpiperidin-1-ylethoxy)phenyl]-N-(2- pyridin-4-ylethyl)thiophene-3-carboxamide 2-[(aminocarbonyl)amino]-5-[4-(2- 40 451 IIIpiperidin-1-ylethoxy)phenyl]-N-(2- pyridin-4-ylethyl)thiophene-3-carboxamide 2-[(aminocarbonyl)amino]-N-azetidin- 41 347 III3-yl-5-(4-methoxyphenyl)thiophene-3- carboxamide2-[(aminocarbonyl)amino]-5-(4- 42 375 1.71(m, 1H), 1.92(m, 2H), IIImethoxyphenyl)-N-[(2S)-pyrrolidin-2- 2.04(m, 1H), 3.33-3.11(m, 2H),ylmethyl]thiophene-3-carboxamide 3.62-3.45(m, 2H), 3.76(s, 3H), 6.97(d,2H, J=8.84Hz), 7.45(d, 2H, J=8.59Hz), 7.52(s, 1H), 7.94(s, 1H), 8.47(t,1H, J=5.81Hz), 8.52(brs, 1H), 9.15(brs, 1H), 10.79(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 43 369 3.78(s, 3H), 7.01(d, 2H), IIImethoxyphenyl)-N-pyridin-4- 7.52(d, 2H), 7.79(s, 1H), 8.15(d,ylthiophene-3-carboxamide 2H), 8.70(brs, 2H), 10.62(s, 1H), 10.68(brs,1H) 2-[(aminocarbonyl)amino]-5-(4- 44 404 2.06(m, 4H), 2.34(brs, 2H),III methoxyphenyl)-N-(2-piperazin-1- 2.42(m, 2H), 2.67(m, 4H),ylethyl)thiophene-3-carboxamide 3.76(s, 3H), 6.97(d, 2H, J=8.84Hz),7.44(d, 2H, J=8.59Hz), 7.55(s, 1H), 8.10(t, 1H, J-5.68Hz), 10.95(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 45 403 1.37(s, 2H), 1.48(s, 4H), IIImethoxyphenyl)-N-(2-piperidin-1- 2.37(brs, 4H), 2.42(t, 2H), 3.76(s,ylethyl)thiophene-3-carboxamide 3H), 6.94(brs, 1H), 6.97(d, 2H), 7.44(d,2H), 7.56(t, 2H), 8.11(t, 1H), 10.96(s, 1H)2-[(aminocarbonyl)amino]-N-1- 46 401 III azabicyclo[2.2.2]oct-3-yl-5-(4-methoxyphenyl)thiophene-3- carboxamide 2-[(aminocarbonyl)amino]-N-(2- 48322 3.06(t, 1H), 3.5(m, 2H), III hydroxyethyl)-5-(4- 6.54(bs, 1H),6.78-6.97(m, 4H), hydroxyphenyl)thiophene-3- 7.33(m, 2H), 7.49(s, 1H),carboxamide 8.34(m, 1H), 9.56(s, 1H), 10.94(s, 1H)2-[(aminocarbonyl)amino]-N-(trans-4- 49 390 1.10-1.45(dq, 4H), 1.85(t,4H), III hydroxycyclohexyl)-5-(4- 3.40(brs, 1H), 3.71(brm, 1H),methoxyphenyl)thiophene-3- 3.76(s, 3H), 4.56(brs, 1H), carboxamide6.90(brs, 1H), 6.96(d, 2H), 7.45(d, 2H), 7.62(s, 1H), 7.81(d, 1H),11.03(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 50 383 3.17(t, 2H,J=6.44Hz), III hydroxyphenyl)-N-(2-pyridin-4- 3.64(m, 2H), 6.77(d, 2H,J=8.59Hz), ylethyl)thiophene-3-carboxamide 7.31(d, 2H, J=8.59Hz),7.45(s, 1H), 7.97(d, 2H, J=6.32Hz), 8.27(s, 1H), 8.83(d, 2H, J=6.06Hz),10.79(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 52 525 1.34-1.58(m, 2H),1.75(t, 2H, III methoxyphenyl)-N-(2-piperazin-1- J=14.02Hz), 1.98(brs,1H), ylethyl)thiophene-3-carboxamide 2.01(d, 1H), 2.80(m, 3H), 3.48(d,2H, J=8.59Hz), 3.73(s, 6H), 3.75(s, 3H), 6.63(dd, 2H, J1=8.34Hz,J2=4.80Hz), 6.90(brs, 1H), 6.95(d, 2H, J=8.59Hz), 7.21(t, 2H), 7.45(d,2H, J=8.84Hz), 7.46(s, 1H), 7.86(d, 1H, J=7.58Hz), 11.00(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 54 397 3.12(t, 2H), 3.62(t, 2H), IIImethoxyphenyl)-N-(2-pyridin-4- 3.76(s, 3H), 6.97(d, 2H), 7.42(d,ylethyl)thiophene-3-carboxamide 2H), 7.49(s, 1H), 7.85(d, 2H), 8.28(s,1H), 8.78(d, 2H), 10.84(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 55 3833.17(t, 2H, J=6.44Hz), III hydroxyphenyl)-N-(2-pyridin-3- 3.64(m, 2H),6.77(d, 2H, J=8.59Hz), ylethyl)thiophene-3-carboxamide 7.31(d, 2H,J=8.59Hz), 7.45(s, 1H), 7.97(d, 2H, J=6.32Hz), 8.27(s, 1H), 8.83(d, 2H,J=6.06Hz), 10.79(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 56 397 2.99(t,2H), 3.55(m, 2H), III methoxyphenyl)-N-(2-pyridin-3- 3.76(s, 3H),6.97(d, 2H), 7.42(d, ylethyl)thiophene-3-carboxamide 2H), 7.50(s, 1H),7.76(m, 1H), 8.16(d, 1H), 8.25(s, 1H), 8.65(s, 1H), 8.69(s, 1H),10.85(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 58 431 1.44(s, 12H), 1.63(t,2H), III methoxyphenyl)-N-(2,2,6,6- 1.95(d, 2H), 3.76(s, 3H), 4.34(brs,tetramethylpiperidin-4-yl)thiophene-3- 1H), 6.96(d, 2H), 7.45(d, 2H),carboxamide 7.67(s, 1H), 8.12(m, 2H), 9.06(bd, 1H), 10.92(s, 1H)2-[(aminocarbonyl)amino]-5-(2- 59 375 III methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide 2-[(aminocarbonyl)amino]-5-(4- 60 376 1.52(m,1H), 1.77(m, 3H), III methoxyphenyl)-N-(tetrahydrofuran-2- 3.25(m, 2H),3.72(m, 1H), ylmethyl)thiophene-3-carboxamide 3.71(s, 3H), 3.93(m, 2H),6.91(bd, 4H, J=8.84Hz), 7.39(d, 2H, J=8.59Hz), 7.59(s, 1H), 8.17(bs,1H), 10.91(s, 1H) tert-butyl (3R)-3-({[2- 62 475 1.38(s, 9H),1.47-1.99(brm, III [(aminocarbonyl)amino]-5-(4- 6H), 3.56(brm, 2H),3.74(brm, methoxyphenyl)-3- 1H), 3.76(s, 3H), 6.96(d, 2H,thienyl]carbonyl}amino)piperidine-1- J=8.59Hz), 7.45(d, 2H, J=8.84Hz),carboxylate 7.62(s, 1H), 7.85(brs, 1H), 8.77(d, 1H, J=7.58Hz), 10.96(s,1H 2-[(aminocarbonyl)amino]-5-(4- 63 383 3.76(s, 3H), 4.48(d, 2H), IIImethoxyphenyl)-N-(pyridin-3- 6.96(d, 2H), 7.36(dd, 1H), 7.44(d,ylmethyl)thiophene-3-carboxamide 2H), 7.61(s, 1H), 7.72(dt, 1H),8.46(bdd, 1H), 8.56(bd, 1H), 8.77(t, 1H) tert-butyl 3-({[2- 64 4471.39(s, 9H), 3.77(s, 3H), III [(aminocarbonyl)amino]-5-(4- 3.86(m, 2H),4.13(t, 2H, J=7.83Hz), methoxyphenyl)-3- 4.61(m, 1H), 6.97(d, 2H,thienyl]carbonyl}amino)azetidine-1- J=8.84Hz), 7.45(d, 2H, J=8.59Hz),carboxylate 7.60(s, 1H), 8.57(d, 1H, J=6.82Hz), 10.82(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 65 383 III methoxyphenyl)-N-(pyridin-4-ylmethyl)thiophene-3-carboxamide 2-[(aminocarbonyl)amino]-5-(4- 67 3641.76(m, 2H), 3.23(s, 3H), III methoxyphenyl)-N-(3- 3.30(t, 2H), 3.37(t,2H), 3.76(s, methoxypropyl)thiophene-3- 3H), 6.96(d, 2H), 7.44(d, 2H),carboxamide 7.57(s, 1H), 8.15(brs, 1H), 10.97(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 68 402 III methoxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide 2-[(aminocarbonyl)amino]-5-(4- 69388 3.76(s, 3H), 4.62(d, 2H), III methoxyphenyl)-N-(2- 6.96(d, 1H),6.96(d, 2H), 7.03(d, thienylmethyl)thiophene-3- 1H), 7.39(d, 1H),7.43(d, 2H), carboxamide 7.60(s, 1H), 8.79(t, 1H), 10.92(s, 1H)N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4- 70 375 7.50 d J=8.8Hz 2H, 7.09 s1H, III methoxyphenyl)-2-thienyl]urea 6.95 d J=8.8Hz 2H, 3.86 s 3H,1.23-1.35 m 6H. 2-[(aminocarbonyl)amino]-N-(2- 71 350 3.27(s, 3H),3.37-3.51(m, 4H), III methoxyethyl)-5-(4- 3.76(s, 3H), 6.97(d, 2H),methoxyphenyl)thiophene-3- 7.44(d, 2H), 7.61(s, 1H), carboxamide8.15-8.26(m, 1H), 10.95(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 72 3744.61(d, 2H, J=5.81Hz), III hydroxyphenyl)-N-(2- 6.77(d, 2H, J=8.59Hz),6.96(dd, thienylmethyl)thiophene-3- 2H, J1=5.05Hz, J2=3.54Hz),carboxamide 7.02(d, 1H, J=3.03Hz), 7.32(d, 2H, J=8.34Hz), 7.38(d, 1H,J=5.05Hz), 7.53(s, 1H), 8.77(t, 1H, J=5.81Hz), 9.53(s, 1H), 10.89(s, 1H)2-[(aminocarbonyl)amino]-N-{2-[(2- 74 432 2.61(t, 2H), 2.65(t, 2H), IIIfurylmethyl)thio]ethyl}-5-(4- 3.75(s, 3H), 3.81(d, 2H), 6.29(d,methoxyphenyl)thiophene-3- 1H, J=3.03Hz), 6.38(dd, 1H, carboxamideJ1=3.03Hz, J2=1.77Hz), 6.97(d, 2H, J=8.84Hz), 7.44(d, 2H, J=8.84Hz),7.55(s, 1H), 7.57(brs, 1H), 8.31(t, 1H, J=5.68Hz), 9.10(t, 1H,J=4.93Hz), 10.92(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 75 388 3.50(m,2H), 3.80(m, 2H), III hydroxyphenyl)-N-[2-(2- 6.54(bs, 1H), 6.78-7.34(m,7H), thienyl)ethyl]thiophene-3-carboxamide 7.49(s, 1H), 8.34(m, 1H),9.56(s, 1H), 10.94(s, 1H) N-(3-[(4-aminopiperidin-1-yl)carbonyl]- 76 460MeOD; 7.24(dd, 1H), 7.16(dd, III 5-{3-[2-(diethylamino)ethoxy]phenyl}-1H), 7.08(s, 1H), 7.06(s, 1H), 2-thienyl)urea trifluoroacetate 6.83(dd,1H), 4.34(m, 2H), 4.30(dd, 2H), 3.53(dd, 2H), 3.32(m, 1H), 3.27(q, 4H),3.04(m, 2H), 1.99(m, 2H), 1.50(m, 2H), 1.28(t, 6H)2-[(aminocarbonyl)amino]-5-(4- 77 389 1.22(dd, 1H, J1=12.38Hz, IIImethoxyphenyl)-N-[(3R)-piperidin-3- J2=2.53Hz), 1.57(d, 1H,ylmethyl]thiophene-3-carboxamide J=13.14Hz), 1.78(brt, 2H), 1.95(brs,1H), 2.60(q, 1H, J=11.37), 2.78(q, 1H, J=10.61Hz), 3.09(m, 1H), 3.25(m,3H), 3.77(s, 3H), 6.97(d, 2H, J=8.59Hz), 7.44(d, 2H, J=8.84Hz), 7.58(s,1H), 8.24(brs, 1H), 8.30(brt, 1H), 8.57(brs, 1H), 10.92(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 78 423 III methoxyphenyl)-N-(1,2,3,4-tetrahydroquinolin-3-yl)thiophene-3- carboxamide2-[(aminocarbonyl)amino]-N-(1,3- 79 426 3.76(s, 3H), 4.36(d, 2H), IIIbenzodioxol-5-ylmethyl)-5-(4- 5.97(s, 2H), 6.81(d, 1H), 6.89(d,methoxyphenyl)thiophene-3- 1H), 6.96(d, 2H), 7.44(d, 2H), carboxamide7.62(s, 1H), 8.64(t, 1H), 10.94(s, 1H) 2-[(aminocarbonyl)amino]-N-(3- 80412 3.74(s, 3H), 3.78(s, 3H), III methoxybenzyl)-5-(4- 4.44(d, 2H,J=5.56Hz), methoxyphenyl)thiophene-3- 6.82(m, 1H), 6.91(m, 2H),carboxamide 6.98(d, 2H, J=8.59Hz), 7.25(t, 2H, J=7.83), 7.46(d, 2H,J=8.59Hz), 7.66(s, 1H), 8.71(s, 1H), 10.95(s, 1H)2-[(aminocarbonyl)amino]-N-[2-(3,4- 81 456 3.73(s, 3H), 3.74(s, 3H), IIIdimethoxyphenyl)ethyl]-5-(4- 3.77(s, 3H), methoxyphenyl)thiophene-3-4.40(d, 2H, J=5.56Hz), carboxamide 6.92(m, 7H), 7.45(d, 2H, J=8.84Hz),7.66(s, 1H), 8.64(bs, 1H), 10.97(s, 1H) 2-[(aminocarbonyl)amino]-5-(4-84 386 2.22(s, 3H), 3.76(s, 3H), III methoxyphenyl)-N-[(5-methyl-2-4.38(d, 2H), 5.99(s, 1H), 6.14(s, furyl)methyl]thiophene-3-carboxamide1H), 6.96(d, 2H), 7.43(d, 2H), 7.64(s, 1H), 8.57(t, 1H), 10.93(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 85 383 3.77(s, 3H), 4.69(d, 2H), IIImethoxyphenyl)-N-(pyridin-2- 6.98(d, 2H), 7.46(d, 2H), 7.65(t,ylmethyl)thiophene-3-carboxamide 1H), 7.73(t, 1H), 7.67(s, 1H), 8.20(t,1H), 8.69(d, 1H), 8.96(t, 1H), 10.76(s, 1H)2-[(aminocarbonyl)amino]-N-(4- 86 400 III fluorobenzyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide tert-butyl 4-({[2- 88 475 III[(aminocarbonyl)amino]-5-(3- methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate2-[(aminocarbonyl)amino]-N-(2- 89 412 3.78(s, 3H), 3.83(s, 3H), IIImethoxybenzyl)-5-(4- 4.45(bd, 2h, J=5.56Hz), methoxyphenyl)thiophene-3-6.97(m, 5H(, 7.23(m, 2H), carboxamide 7.47(d, 2H, J=8.84), 7.71(s, 1H),8.55(bt, 1H), 10.97(s, 1H) 2-[(aminocarbonyl)amino]-5-(4- 90 4123.56-3.7(m, 2H), 3.76(s, 3H), III methoxyphenyl)-N-(2- 4.11(t, 2H),6.85-7.05(m, 5H), phenoxyethyl)thiophene-3- 7.28(t, 2H), 7.44(d, 2H),carboxamide 7.61(s, 1H), 8.38(brs, 1H), 10.93(s, 1H)2-[(aminocarbonyl)amino]-5-(4- 93 397 3.00(t, 2H, J=7.45Hz), IIImethoxyphenyl)-N-(2-pyridin-2- 3.61(m, 2H), 3.76(s, 3H), 6.97(d,ylethyl)thiophene-3-carboxamide 2H, J=8.84Hz), 7.22(dd, 1H, J1=6.95Hz,J2=5.18Hz), 7.27(d, 1H, J=7.83Hz), 7.43(d, 2H, J=8.59Hz), 7.54(s, 1H),7.70(dt, 1H, J1=7.58Hz, J2=1.77Hz), 8.27(t, 1H, J=5.56Hz), 8.51(d, 1H,J=4.55Hz), 10.97(s, 1H) tert-butyl 4-({[2- 94 475 III[(aminocarbonyl)amino]-5-(4- methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate2-[(aminocarbonyl)amino]-N-(4- 95 412 3.72(s, 3H), 3.76(s, 3H), IIImethoxybenzyl)-5-(4- 4.39(d, 2H), 6.89(d, 2H), 6.96(d,methoxyphenyl)thiophene-3- 2H), 7.25(d, 2H), 7.44(d, 2H), carboxamide7.63(s, 1H), 8.64(t, 1H), 10.95(s, 1H) 2-[(aminocarbonyl)amino]-5-{4-[2-110 460 MeOD; 7.55(d, 2H), 7.45(s, 1H), IV(diethylamino)ethoxy]phenyl}-N-[(3S)- 7.05(d, 2H), 4.35(dd, 2H),piperidin-3-yl]thiophene-3- 4.25(m, 1H), 3.60(dd, 2H), carboxamidetrifluoroacetate 3.50(m, 1H), 3.30(m, 5H), 2.95(dd, 2H), 2.10(dd, 2H),1.80(m, 2H), 1.35(t, 6H) 2-[(aminocarbonyl)amino]-5-{4-[2- 111 460 MeOD;7.55(d, 2H), 7.45(s, 1H), IV (diethylamino)ethoxy]phenyl}-N-[(3R)-7.05(d, 2H), 4.35(dd, 2H), piperidin-3-yl]thiophene-3- 4.25(m, 1H),3.60(dd, 2H), carboxamide trifluoroacetate 3.50(m, 1H), 3.30(m, 5H),2.95(dd, 2H), 2.10(dd, 2H), 1.80(m, 2H), 1.35(t, 6H) tert-butyl(3S)-3-{[(2- 112 560 MeOD; 7.55(d, 2H), 7.45(s, 1H), IV[(aminocarbonyl)amino]-5-{4-[2- 7.05(d, 2H), 4.35(dd, 2H),(diethylamino)ethoxy]phenyl}-3- 3.60-3.90(m, 3H), 3.60(dd, 2H),thienyl)carbonyl]amino}piperidine-1- 3.30(m, 4H), 2.95(m, 2H),carboxylate trifluoroacetate 1.90(dd, 2H), 1.55(m, 2H), 1.45(s, 9H),1.35(t, 6H) 2-[(aminocarbonyl)amino]-N-[(3S)- 113 474 10.85(s, 1H),9.50(br s, 1H), IV azepan-3-yl]-5-{4-[2- 9.10(br s, 1H), 8.95(br s, 1H),(diethylamino)ethoxy]phenyl}thiophene- 8.20(d, 1H), 7.65(s, 1H), 7.50(d,3-carboxamide hydrochloride 2H), 7.05(d, 2H), 6.95, (br s 2H), 4.35(dd,2H), 4.25(m, 1H), 3.50(dd, 2H), 3.10-3.40(m, 8H), 2.00(m, 1H), 1.80(m,4H), 1.55(m, 1H), 1.25(t, 6H) tert-butyl (3R)-3-{[(2- 114 560 MeOD;7.45(d, 2H), 7.35(s, 1H), IV [(aminocarbonyl)amino]-5-{4-[2- 6.90(d,2H), 4.25(dd, 2H), (diethylamino)ethoxy]phenyl}-3- 3.60-3.90(m, 3H),3.50(dd, 2H), thienyl)carbonyl]amino}piperidine-1- 3.20(m, 5H), 2.85(s,1H), carboxylate trifluoroacetate 1.80(dd, 2H), 1.45(m, 2H), 1.35(s,9H), 1.25(t, 6H) N-[3-{[(3S)-3-aminoazepan-1- 115 389 9.65(s, 1H),8.25(s, 3H), IV yl]carbonyl}-5-(4-methoxyphenyl)-2- 7.50(d, 2H), 7.10(s,1H), 6.90(d, thienyl]urea hydrochloride 2H), 6.75(br s, 2H), 4.00(m,1H), 3.80(s, 3H), 3.40(m, 4H), 2.0(m, 1H), 1.00-1.80(m, 5H) 2-({[(2,5-116 511 11.28 s 1H, 9.65 bs 1H, 9.08 bs Vdimethoxyphenyl)amino]carbonyl}amino)- 1H, 8.43 s 1H, 7.90 s 1H, 7.465-(4-methoxyphenyl)-N-piperidin-3- d J=8.7Hz 2H, 6.83 d J=8.8Hzylthiophene-3-carboxamide 2H, 6.65 d J=8.8Hz 1H, 6.43-6.47 m 1H, 4.35 bs1H, 3.76 s 3H, 7.73 s 3H, 3.54 s 3H, 3.24-3.45 m 2H, 2.81 bs 2H, 2.44 bs4H. 5-{4-[2-(diethylamino)ethoxy]phenyl}- 120 524 1.21(t, 6H), 2.00(m,1H), VI 2-{[(pyrazin-2- 2.20(m, 1H), 3.18(m, 4H), 3.43(m,ylamino)carbonyl]amino}-N-[(3S)- 6H), 4.31(t, 2H), 4.53(m, 1H),pyrrolidin-3-yl]thiophene-3- 7.05(d, 2H), 7.52(d, 2H), carboxamide7.70(s, 1H), 8.30(m, 3H), 8.78(s, 1H), 8.85(s, 1H), 8.98(s, 1H), 9.32(s,1H), 10.90(s, 1H) 5-{3-[2-(diethylamino)ethoxy]phenyl}- 121 524 1.25(t,6H), 2.02(m, 1H), VI 2-{[(pyrazin-2- 2.20(m, 1H), 3.22(m, 4H), 3.43(m,ylamino)carbonyl]amino}-N-[(3S)- 6H), 4.34(t, 2H), 4.53(m, 1H),pyrrolidin-3-yl]thiophene-3- 6.92(d, 1H), 7.12(s, 1H), carboxamidehydrochloride 7.28(d, 1H), 7.39(dxd, 1H), 7.84(s, 1H), 8.32(m, 3H),8.78(s, 1H), 8.85(s, 1H), 8.98(s, 1H), 9.30(s, 1H), 10.92(s, 1H)5-{3-[2-(diethylamino)ethoxy]phenyl}- 122 538 ): 0.95(t, 6H), 1.52(m,2H), VI N-piperidin-4-yl-2-{[(pyrazin-2- 1.62(m, 4H), 2.52(m, 4H),ylamino)carbonyl]amino}thiophene-3- 2.78(m, 4H), 3.00(m, 12H), 3.18(t,carboxamide 2H), 4.05(t, 2H), 6.68(bs, 1H), 6.80(d, 1H), 7.10(m, 2H),7.28(m, 2H), 7.82(s, 1H), 8.22(s, 1H), 8.28(s, 1H), 9.00(s, 1H)N-[(3S)-azepan-3-yl]-5-(4- 123 467 δ 12.6, br s, 1H; δ 10.9, s, 1H; VImethoxyphenyl)-2-{[(pyrazin-2- δ 9.55, br s, 1H; δ 9.24, br s,ylamino)carbonyl]amino}thiophene-3- 1H; δ 8.88, s, 1H; δ 8.49, d,carboxamide hydrochloride 1H; δ 8.35, dd, 1H; δ 8.29, d, 1H; δ 7.92, s,1H; δ 7.54, d, 2H; δ 6.99, d, 2H; δ 4.42, m, 1H; δ 3.33, m, 1H; δ 3.23,m, 2H; δ 3.10, m, 1H; δ 2.02, m, 1H; δ 1.85, m, 4H; δ 1.62, m, 1H5-{3-[2-(diethylamino)ethoxy]phenyl}- 124 538 0.95(t, 6H), 1.52(m, 2H),VI N-piperidin-3-yl-2-{[(pyrazin-2- 1.62(m, 4H), 2.52(m, 4H), 2.78(m,ylamino)carbonyl]amino}thiophene-3- 4H), 3.00(m, 12H), 3.18(t, 2H),carboxamide hydrochloride 4.05(t, 2H), 6.68(bs, 1H), 6.80(d, 1H),7.10(m, 2H), 7.28(m, 2H), 7.82(s, 1H), 8.22(s, 1H), 8.28(s, 1H), 9.00(s,1H) N-(2-aminoethyl)-5-(4-methoxyphenyl)- 125 413 8.53 s 1H, 8.31-8.33 m1H, 8.13 VI 2-{[(pyrazin-2- d J=2.8Hz 1H, 7.42 d J=8.8Hzylamino)carbonyl]amino}thiophene-3- 2H, 7.38 s 1H, 6.85 d J=8.8Hzcarboxamide 2H, 3.72 s 3H. 5-{4-[2-(diethylamino)ethoxy]phenyl}- 126 5380.95(t, 6H), 1.52(m, 2H), VI N-piperidin-3-yl-2-{[(pyrazin-2- 1.79(m,2H), 2.42(m, 4H), 2.70(m, ylamino)carbonyl]amino}thiophene-3- 4H),3.08(m, 2H), 3.98(m, 3H), carboxamide 6.95(d, 2H), 7.48(d, 2H), 7.70(s,1H), 8.28(d, 2H), 8.95(s, 1H) 5-(4-methoxyphenyl)-N-piperidin-4-yl- 127453 VI 2-{[(pyrazin-2- ylamino)carbonyl]amino}thiophene-3- carboxamidetert-butyl 3-{[(5-{3-[2- 128 638 1.21(t, 6H), 1.32(s, 9H), VI(diethylamino)ethoxy]phenyl}-2- 1.75(m, 1H), 1.92(m, 1H), 2.85(m,{[(pyrazin-2-ylamino)carbonyl]amino}- 1H), 3.20(m, 4H), 3.50(t, 2H),3-thienyl)carbonyl]amino}piperidine-1- 3.80(m, 2H), 4.35(t, 2H),carboxylate trifluoroacetate 6.90(d, 1H), 7.15(s, 1H) 7.25(d, 1H),7.38(dxd, 1H), 7.76(s, 1H), 7.98(bs, 1H), 8.30(d, 2H), 8.90(s, 1H),9.25(bs, 1H), 10.92(s, 1H) 5-{4-[2-(diethylamino)ethoxy]phenyl}- 129 5380.95(t, 6H), 1.52(m, 2H), VI N-piperidin-4-yl-2-{[(pyrazin-2- 1.79(m,2H), 2.42(m, 4H), 2.70(m, ylamino)carbonyl]amino}thiophene-3- 4H),3.08(m, 2H), 3.98(m, 3H), carboxamide 6.95(d, 2H), 7.48(d, 2H), 7.70(s,1H), 8.28(d, 2H), 8.95(s, 1H) 5-(4-methoxyphenyl)-2-{[(pyrazin-2- 130439 VI ylamino)carbonyl]amino}-N-[(3S)- pyrrolidin-3-yl]thiophene-3-carboxamide N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4- 131 453 8.47 s 1H,8.14-8.25 m 2H, 7.43 VI methoxyphenyl)-2-thienyl]-N′-pyrazin- d J=8.8Hz2H, 7.06 s 1H, 7.85 2-ylurea d J=8.8Hz 2H, 3.90 bs 2H, 3.79 t J=6.0Hz2H, 3.72 s 3H, 3.40 bs 2H, 2.10 bs 2H. N-[3-[(3-aminopyrrolidin-1- 132439 11.97 bs 1H, 10.72 s 1H, 8.79 s VIyl)carbonyl]-5-(4-methoxyphenyl)-2- 1H, 8.22-8.26 m 2H, 7.50 dthienyl]-N′-pyrazin-2-ylurea J=8.6Hz 2H, 8.04 bs 2H, 7.31 s 1H,7.20-7.25 m 2H, 7.08 d J=8.3Hz 1H, 7.00 t J=7.2Hz 1H, 6.92 d J=8.6Hz2H3.72 s 3H, 2.11-2.19 m 1H, 3.80 bs 2H, 3.64 bs 2H. tert-butyl4-{[(5-(4-methoxyphenyl)-2- 133 553 VI{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1- carboxylate tert-butyl3-{[(5-{4-[2- 134 638 1.18(t, 6H), 1.32(s, 9H), VI(diethylamino)ethoxy]phenyl}-2- 1.72(m, 1H), 1.90(m, 1H), 2.85(m,{[(pyrazin-2-ylamino)carbonyl]amino}- 1H), 3.21(m, 4H), 3.50(t, 2H),3-thienyl)carbonyl]amino}piperidine-1- 3.80(m, 2H), 4.30(t, 2H),carboxylate 7.05(d, 2H), 7.52(d, 2H), 7.76(s, 1H), 7.92(bs, 1H), 8.30(d,2H), 8.90(s, 1H), 9.25(bs, 1H), 10.90(s, 1H)5-[4-(2-diethylamino-ethoxy)-phenyl]-2- 136 476 δ 1.17-1.40(m, 6H) VII(3-hydroxy-urea)-thiophene-3- 1.54-1.81(m, 2H) 1.84-2.07(m, 2H)carboxylic acid-(S)-piperidin-3-ylamide 2.76-2.99(m, 2H) 3.05-3.25(m,4H) 3.41-3.61(m, 4H) 3.73-3.88(m, 1H) 4.29-4.42(m, 1H) 4.40-4.64(m, 1H)5.86(s, 1H) 7.07(d, J=8.48Hz, 2H) 7.55(d, J=8.48Hz, 2H) 7.82(s, 1H)9.44(s, 1H) 9.65(s, 1H); 2-[(aminocarbonyl)amino]-N-[(3S)- 137 38910.90(s, 1H), 9.21(s, 1H), VIII azepan-3-yl]-5-(3- 9.01(s, 1H), 8.29(d,1H), 7.93(s, methoxyphenyl)thiophene-3- 1H), 7.29(t, 1H), 7.11(d, 2H),carboxamide 7.03(s, 1H), 6.83(d, 1H), 4.33(s, 1H), 3.81(s, 3H), 3.20(m,4H), 2.00(m, 1H), 1.84(m, 4H), 1.56(m, 1H).2-[(aminocarbonyl)amino]-5-(2- 138 361 δ 10.85(s, 1H), 10.13(s, 1H),VIII hydroxyphenyl)-N-[(3S)-piperidin-3- 9.29(d, 2H), 8.31(d, 1H),yl]thiophene-3-carboxamide 7.92(s, 1H), 7.63(dd, 1H), 7.05(td, 1H),6.94(dd, 1H), 6.82(td, 1H), 6.91(brs, 2H), 4.21(brs, 1H), 3.26(dd, 2H),2.89(m, 2H), 1.88-1.618(m, 4H). 2-[(aminocarbonyl)amino]-5-(3- 139 37510.94(s, 1H), 9.41(s, 1H), VIII methoxyphenyl)-N-[(3S)-piperidin-3-9.19(s, 1H), 8.47(d, 1H), 8.11(s, yl]thiophene-3-carboxamide 1H),7.30(t, 1H), 7.15(d, 1H), 7.05(br, 2H), 6.84(d, 1H), 4.25(s, 1H),3.82(s, 3H), 3.29(d, 1H), 3.12(d, 1H), 2.97(m, 2H), 1.92(d, 2H), 1.69(m,2H). 2-[(aminocarbonyl)amino]-5-[2- 140 451 δ 10.8(s, 1H), 8.63(brs,2H), VIII (benzyloxy)phenyl]-N-[(3S)-piperidin-3- 8.04(d, 1H), 7.79(s,1H), yl]thiophene-3-carboxamide 7.63(d, 1H), 7.55(d, 2H), 7.38(t, 2H),7.31(t, 1H), 7.23(t, 1H), 7.20(t, 1H), 7.02(t, 1H), 6.95(m, 2H), 5.28(s,2H), 4.15(m, 1H), 3.24(m, 1H), 2.85(m, 2H), 1.90-1.58(m, 5H).

TABLE 2 M.W. Structure IUPAC Name (g/mol) Ex.

tert-butyl 3-{[(2- [(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate trifluoroacetate 559.7 1

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide trifluoroacetate 459.6 2

2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide trifluoroacetate 459.6 3

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3- carboxamide 374.5 4

tert-butyl 3-{[(2-[(amino- carbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate trifluoroacetate 559.7 5

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-thiophene-3-carboxamide 459.6 6

2-[(aminocarbonyl)amino]-N- [(3R)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3- carboxamide 388.5 7

N-(3-[(4-aminopiperidin-1-yl) carbonyl]-5-{4-[2-(diethyl-amino)ethoxy]phenyl}-2- thienyl)urea trifluoroacetate 459.6 8

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxy-methyl)phenyl]thiophene-3- carboxamide trifluoroacetate (salt) 482.6 9

2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-ylthiophene-3-carboxamide trifluoroacetate 459.6 10

2-[(aminocarbonyl)amino]-N- (2-aminoethyl)-5-(4-methoxy-phenyl)thiophene-3- carboxamide 334.4 11

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-piperidin-4-ylthiophene-3- carboxamide 374.5 12

2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide trifluoroacetate 453.6 13

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(1-methylpiperidin-4-yl) thiophene-3-carboxamide 388.5 14

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3S)-1-methylazepan-3-yl]thiophene- 3-carboxamide hydrochloride 402.5 15

2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxy-methyl)phenyl]thiophene-3- carboxamide trifluoroacetate (salt) 482.6 16

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide trifluoroacetate 445.6 17

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide trifluoroacetate 453.6 18

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3S)-1-methylpiperidin-3-yl]thiophene-3-carboxamide hydrochloride 388.5 19

2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide trifluoroacetate 445.6 20

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide 388.5 21

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3S)-pyrrolidin-3-yl]thiophene-3- carboxamide 360.4 22

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]thiophene-3- carboxamide 360.4 23

2-[(aminocarbonyl)amino]-N- [2-(dimethylamino)ethyl]-5-(4-methoxyphenyl)thiophene- 3-carboxamide 362.4 24

2-[(aminocarbonyl)amino]-N- [2-(diethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3- carboxamide 390.5 25

2-[(aminocarbonyl)amino]-N- [(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3- carboxamide hydrochloride 388.5 26

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]thiophene-3- carboxamide 374.5 27

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N- (piperidin-4-ylmethyl)thiophene-3-carboxamide 388.5 28

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-pyrrolidin-3-ylthiophene-3- carboxamide 360.4 29

2-[(aminocarbonyl)amino]-N- (1-ethylpiperidin-3-yl)-5-(4-methoxyphenyl)thiophene-3- carboxamide hydrochloride 402.5 30

2-[(aminocarbonyl)amino]-N- [(3S)-1-ethylazepan-3-yl]-5-(4-methoxyphenyl)thiophene- 3-carboxamide hydrochloride 416.5 31

2-[(aminocarbonyl)amino]-5- (3-hydroxyphenyl)-N-piperidin-4-ylthiophene-3- carboxamide 360.4 32

2-[(aminocarbonyl)amino]-5- (4-hydroxyphenyl)-N-piperidin-4-ylthiophene-3- carboxamide 360.4 33

2-[(aminocarbonyl)amino]-5- (3-methoxyphenyl)-N-piperidin-4-ylthiophene-3- carboxamide 374.5 34

tert-butyl (3S)-3-({[2- [(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)pyrrolidine- 1-carboxylate 460.635

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-piperidin-3-ylthiophene-3- carboxamide 374.5 36

2-[(aminocarbonyl)amino]-N- (1-benzylpiperidin-4-yl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 464.6 37

tert-butyl 3-({[2-[(amino- carbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate 474.638

2-[(aminocarbonyl)amino]-5- [4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4- ylethyl)thiophene-3- carboxamide 493.6 39

2-[(aminocarbonyl)amino]-5- [4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4- ylethyl)thiophene-3- carboxamide 450.6 40

2-[(aminocarbonyl)amino]-N- azetidin-3-yl-5-(4-methoxy-phenyl)thiophene-3- carboxamide 346.4 41

2-[(aminocarbonyl)amino]-N- azetidin-3-yl-5-(4-methoxy-phenyl)thiophene-3- carboxamide 346.4 41

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(2S)-pyrrolidin-2-ylmethyl]thiophene-3-carboxamide 374.5 42

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-pyridin-4-ylthiophene-3-carboxamide 368.4 43

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene- 3-carboxamide 403.5 44

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-piperidin-1-ylethyl)thiophene- 3-carboxamide 402.5 45

2-[(aminocarbonyl)amino]-N- 1-azabicyclo[2.2.2]oct-3-yl-5-(4-methoxyphenyl)thiophene- 3-carboxamide 400.5 46

2-[(aminocarbonyl)amino]-N- (2-hydroxyethyl)-5-(4-hydroxyphenyl)thiophene-3- carboxamide 321.4 48

2-[(aminocarbonyl)amino]-N- (trans-4-hydroxycyclohexyl)-5-(4-methoxyphenyl) thiophene-3-carboxamide 389.5 49

2-[(aminocarbonyl)amino]-5- (4-hydroxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3- carboxamide 382.4 50

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene- 3-carboxamide 524.6 52

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3- carboxamide 396.5 54

2-[(aminocarbonyl)amino]-5- (4-hydroxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3- carboxamide 382.4 55

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3- carboxamide 396.5 56

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2,2,6,6-tetramethylpiperidin- 4-yl)thiophene-3-carboxamide 430.6 58

2-[(aminocarbonyl)amino]-5- (2-methoxyphenyl)-N-piperidin-4-ylthiophene-3- carboxamide 374.5 59

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(tetra-hydrofuran-2-ylmethyl) thiophene-3-carboxamide 375.4 60

tert-butyl (3R)-3-({[2- [(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate 474.662

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N- (pyridin-3-ylmethyl)thiophene-3-carboxamide 382.4 63

tert-butyl 3-({[2-[(amino- carbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azetidine-1- carboxylate 446.564

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N- (pyridin-4-ylmethyl)thiophene-3-carboxamide 382.4 65

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(3-methoxypropyl)thiophene-3- carboxamide 363.4 67

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3- carboxamide 401.5 68

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-thienylmethyl)thiophene-3- carboxamide 387.5 69

N-[3-(1,4-diazepan-1-yl carbonyl)-5-(4-methoxy- phenyl)-2-thienyl]urea374.5 70

2-[(aminocarbonyl)amino]-N- (2-methoxyethyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 349.4 71

2-[(aminocarbonyl)amino]-5- (4-hydroxyphenyl)-N-(2-thienylmethyl)thiophene-3- carboxamide 373.5 72

2-[(aminocarbonyl)amino]-N-{2-[(2-furylmethyl)thio]ethyl}-5-(4-methoxyphenyl)thiophene-3-carboxamide 431.5 74

2-[(aminocarbonyl)amino]-5- (4-hydroxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3- carboxamide 387.5 75

N-(3-[(4-aminopiperidin-1-yl) carbonyl]-5-{3-[2-(diethyl-amino)ethoxy]phenyl}-2- thienyl)urea trifluoroacetate 459.6 76

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide 388.5 77

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinolin-3- yl)thiophene-3-carboxamide 422.5 78

2-[(aminocarbonyl)amino]-N- (1,3-benzodioxol-5-ylmethyl)-5-(4-methoxyphenyl) thiophene-3-carboxamide 425.5 79

2-[(aminocarbonyl)amino]-N- (3-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 411.5 80

2-[(aminocarbonyl)amino]-N- [2-(3,4-dimethoxyphenyl)ethyl]-5-(4-methoxyphenyl) thiophene-3-carboxamide 455.5 81

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-[(5-methyl-2-furyl)methyl]thiophene-3-carboxamide 385.4 84

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N- (pyridin-2-ylmethyl)thiophene-3-carboxamide 382.4 85

2-[(aminocarbonyl)amino]-N- (4-fluorobenzyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 399.4 86

tert-butyl 4-({[2-[(amino- carbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate 474.688

2-[(aminocarbonyl)amino]-N-(2- methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 411.5 89

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-phenoxyethyl)thiophene-3- carboxamide 411.5 90

2-[(aminocarbonyl)amino]-5- (4-methoxyphenyl)-N-(2-pyridin-2-ylethyl)thiophene- 3-carboxamide 396.5 93

tert-butyl 4-({[2-[(amino- carbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1- carboxylate 474.694

2-[(aminocarbonyl)amino]-N- (4-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3- carboxamide 411.5 95

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide trifluoroacetate 459.6 110

2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide trifluoroacetate 459.6 111

tert-butyl (3S)-3-{[(2- [(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate trifluoroacetate 559.7 112

2-[(aminocarbonyl)amino]-N- [(3S)-azepan-3-yl]-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxamide hydrochloride 473.6113

tert-butyl (3R)-3-{[(2- [(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate trifluoroacetate 559.7 114

N-[3-{[(3S)-3-aminoazepan- 1-yl]carbonyl}-5-(4-methoxy-phenyl)-2-thienyl]urea hydrochloride 388.5 115

5-{4-[2-(diethylamino) ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide 523.7 120

5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N- [(3S)-pyrrolidin-3-yl]thiophene-3-carboxamidehydrochloride 523.7 121

5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino) carbonyl]amino}thiophene-3- carboxamide 537.7 122

N-[(3S)-azepan-3-yl]-5-(4- methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide hydrochloride 466.6 123

5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino) carbonyl]amino}thiophene-3- carboxamidehydrochloride 537.7 124

N-(2-aminoethyl)-5-(4- methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide 412.5 125

5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino) carbonyl]amino}thiophene-3- carboxamide 537.7 126

5-(4-methoxyphenyl)-N- piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide 452.5 127

tert-butyl 3-{[(5-{3-[2- (diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate trifluoroacetate 637.8128

5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino) carbonyl]amino}thiophene-3- carboxamide 537.7 129

5-(4-methoxyphenyl)-2- {[(pyrazin-2-ylamino) carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3- carboxamide 438.5 130

N-[3-(1,4-diazepan-1-yl- carbonyl)-5-(4-methoxy-phenyl)-2-thienyl]-N′-pyrazin- 2-ylurea 452.5 131

N-[3-[(3-aminopyrrolidin-1- yl)carbonyl]-5-(4-methoxy-phenyl)-2-thienyl]-N′-pyrazin- 2-ylurea 438.5 132

tert-butyl 4-{[(5-(4-methoxy- phenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate 552.6 133

tert-butyl 3-{[(5-{4-[2- (diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate 637.8 134

5-[4-(2-diethylamino-ethoxy)- phenyl]-2-(3-hydroxy-urea)-thiophene-3-carboxylic acid- (S)-piperidin-3-ylamide 475.2 136

2-[(aminocarbonyl)amino]-N- [(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3- carboxamide 388.5 137

2-[(aminocarbonyl)amino]-5- (2-hydroxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3- carboxamide 360.4 138

2-[(aminocarbonyl)amino]-5- (3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3- carboxamide 374.5 139

2-[(aminocarbonyl)amino]-5- [2-(benzyloxy)phenyl]-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide 450.6 140

Example 42-[(Aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide

(4-Methoxy-phenyl)-acetaldehyde. To a stirred solution of(4-Methoxy-phenyl)-acetic acid methyl ester (18.0 g, 100 mmol) inanhydrous toluene (200 mL) cooled to −78° C. under N₂ was addeddiisobutylaluminum hydride (DIBAL, 1.0 M in toluene, 150 mL, 150 mmol)over a period of 10-15 minutes. The mixture was stirred at −78° C. foran additional 2 h. The reaction was quenched by the slow addition ofMeOH, followed by the introduction of 10% Rochelle's Salt. Thesuspension was diluted with EtOAc and stirred at room temperature for 1h. The EtOAc layer was set aside and the aqueous layer was extractedwith EtOAc(2×). The combined organic layers were combined and dried overNa₂SO₄ and filtered. The solution was concentrated under vacuum to yield12.0 g (100%) of the title aldehyde as a yellow viscous semisolid, whichwas used in the next step without purification. LC/MS (APCI, ES,M+H=151).

2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester.To a solution of 4-methoxyphenylacetaldehyde (12.0 g) in DMF (200 mL)was added cyanomethyl acetate (8.9 mL, 100 mmol) and sulfur (3.2 g, 100mmol), followed by diisopropylethylamine (Hunig's Base, 17.4 mL, 100mmol). The resultant suspension immediately turned dark yellow to brownwith an exotherm. The reaction mixture was stirred overnight at roomtemperature. The reaction was slowly added to water (˜1 L) whilestirring. A tan precipitate formed and was filtered after an additional30 minutes of stirring. The resultant solid was purified by columnchromatography (SiO₂, 10-20% EtOAc/hexanes) to yield 15.3 g (58%) of thetitle compound as a light yellow solid. ¹H NMR (d₆-DMSO δ 7.41, br s,2H; δ 7.37, d, 2H; δ 7.07, s, 1H; δ 6.90, d, 2H; δ 3.75, s, 3H; δ 3.72,s, 3H), LC/MS (APCI, ES, M+H=264).

Methyl5-(4-methoxyphenyl)-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate.To a stirred solution of2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid methyl ester(7.15 g, 27.2 mmol) in anhydrous THF (150 mL) was added trichloroacetylisocyanate (6.4 mL, 54 mmol) slowly over a period of 5 min. After theaddition was complete, a precipitate formed and the reaction stirred foran additional 1 h. The desired product was obtained by filtration togive 6.9 g (56%) an off-white solid. The product was used in the nextstep without purification ¹H NMR (d₆-DMSO δ 12.3, br s, 1H; δ 12.2, s,1H; δ 7.46, d, 2H; δ 7.32, s, 1H; δ 6.85, d, 2H; δ 3.75, s, 3H; δ 3.66,s, 3H), LC/MS (APCI, ES, M+H=451).

tert-Butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate.To a solution of methyl5-(4-methoxyphenyl)-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate(1.0 g, 2.2 mmol) in dry THF (20 mL) was added a solution of[Me₂Al-3-Boc-(S)-3-aminopiperidine] in THF (which was preformed by theaddition of Me₃Al (2.0 M in hexanes, 2.2 nL, 4.4 mmol) to a solution of(S)-3-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 4.4mmol) in 10 mL THF at −78° C. followed by warming to room temperaturefor an additional 15 min). The resulting orange-colored solution wasstirred overnight at room temperature. The reaction mixture was cooledwith ice and a 10% aqueous solution of Rochelle's salt was added slowlyto quench the reaction. The resulting biphasic solution was warmed toroom temperature and stirred for an additional 1 h. The mixture wasdiluted with EtOAc and H₂O, the aqueous layer was extracted with EtOAc(3×) and the combined organic extracts were washed with H₂O, brine anddried (Na₂SO₄). Evaporation gave a pale orange solid. Purification bycolumn chromatography (SiO₂, 50% EtOAc/hexanes) gave 0.70 g (67%) of alight yellow solid. LC/MS (APCI, ES, M+H=475).

2-[(Aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;hydrochloride. To a stirred solution oftert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate(0.70 g, 1.47 mmol) in anhydrous MeOH (5.0 mL) was added 4.0N HCl in1,4-dioxane (10 mL). A small amount of precipitate forms shortly and thereaction is stirred for an additional 4 h at room temperature. Thesolvent was removed under vacuum. The residue was redissolved inmethanol and concentrated under vacuum (2×) to yield 0.51 g (85%) of alight yellow solid. ¹H NMR (d₆-DMSO δ 10.9, s, 1H; δ 9.39, br s, 1H; δ9.20, br s, 1H; δ 8.37, d, 1H; δ 7.88, s, 1H; δ 7.49, d, 2H; δ 6.96, d,2H; δ 6.97, br s, 2H; δ 4.24, m, 1H; δ 3.77, s, 3H; δ 3.29, m, 1H; δ3.11, m, 1H; δ 2.93, m, 2H; δ 1.91, m, 2H; δ 1.68, m, 2H), LC/MS (APCI,ES, M+H=6875).

Example 262-[(Aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamidehydrochloride

(S)-3-Amino-azepane-1-carboxylic acid tert-butyl ester.(S)-Azepan-3-ylamine (5 g; 43.8 mmol) was dissolved in 100 mL ofanhydrous CH₂Cl₂ and cooled to −78° C. while stirring with a magneticstirring bar. In another flask N-(tert-butoxycarbonyloxy)succinimide[Boc-OSu] (9.7 g; 45 mmol) was dissolved in 50 mL of anhydrous CH₂Cl₂.To the stirred solution of the amine was added the solution of thesuccinimide over a period of 10-15 minutes so as to keep the reactionmixture at −78° C. while stirring. After the addition was complete, thereaction was allowed to warm to room temperature and then stirred for anadditional 4 h or until the reaction was complete by TLC (Ninhydrin;R_(f) 0.3; 0.1:1:10 NH₄OH, MeOH; CH₂Cl₂). The reaction mixture waswashed with 50 mL of H₂O. The aqueous layer was brought to a pH >13 bythe addition of 6N NaOH and extracted with CH₂Cl₂ (3×100 mL). Theorganic layer was dried over Na₂CO₃, filtered, and concentracted in avacuum to yield pure (S)-3-amino-azepane-1-carboxylic acid tert-butylester as a viscous oil (5.1 g, 54%). ¹H NMR (d₆-DMSO, d 3.4, m, 2H; d2.89, m, 1H; d 2.71, m, 1H; d 2.54, m, 1H; d 1.54, m, 3H; d 1.34, m, 3H;d 1.27, s, 9H; d 1.12, m, 2H), LC/MS (APCI, ES, M+H=215).

tert-Butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azepane-1-carboxylate.To a solution of methyl5-(4-methoxyphenyl)-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate(1.36 g, 3 mmol) in anhydrous THF (20 mL) was added a solution of[Me₂Al-3-Boc-(S)-3-aminohomopiperidine] in THF (preformed by the carefuladdition of Me₃Al (2.0 M in hexanes, 3.0 mL, 6.0 mmol) to a solution of(S)-3-amino-azepane-1-carboxylic acid tert-butyl ester in 10 nL of THFat −78° C. followed by warming to room temperature under nitrogen andstirring for an additional 15 min.). The resulting deep yellow/orangesolution was stirred overnight at room temperature. The reaction mixturewas cooled with ice and a 10% aqueous solution of Rochelle's salt wasadded slowly to quench the reaction. The resulting biphasic solution waswarmed to room temperature and stirred for an additional 1 h. Themixture was diluted with EtOAc and H₂O, the aqueous layer was extractedwith EtOAc (3×) and the combined organic extracts were washed with H₂O,brine and dried (Na₂SO₄). Evaporation gave a pale orange solid.Purification by ISCO MPLC (SiO₂, 60-80% EtOAc/hexanes) gave 0.9 g (62%)of the title compound as a white solid. ¹H NMR (d₆-DMSO, δ 11.0, s, 1H,δ 7.95, d, 0.5H, δ 7.81, d, 0.5H, δ 7.65, s, 0.5H; δ 7.56, s, 0.5H; δ7.46, d, 2H; δ 6.97, d, 2H; δ 6.96, br s, 2H; δ 4.19, m, 0.5H; δ 4.11,m, 0.5H; δ 3.77, m, 3H; δ 3.65, m, 1H; δ 3.48, m, 1H; δ 3.20, m, 2H; δ1.75, m, 3H; δ 1.58, m, 2H; δ 1.42, s, 4.5H; δ 1.39, m, 1H; δ 1.36, s,4.5H), LC/MS (APCI, ES, M+H=489).

2-[(Aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;hydrochloride. To a stirred solution oftert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azepane-1-carboxylate(0.9 g, 1.8 mmol) in 1,4-dioxane (10 mL) was added 4.0N HCl in1,4-dioxane (10 mL, 40 mmol). A precipitate forms shortly and thereaction is stirred for an additional 4 h at room temperature. Due tothe hygroscopic nature of the salt form, the solvent was removed undervacuum. The residue was dissolved in methanol and concentrated undervacuum (2×) to yield and off-white solid. Recrystallization from using2-propanol gave 0.45 g (59%) of a white solid. ¹H NMR (d₆-DMSO, δ 10.9,s, 1H; δ 9.58, br s, 1H; δ 9.29, br s, 1H; δ 8.39, d, 1H; δ 7.82, s, 1H;δ 7.48, d, 2H; δ 6.96, d, 2H; δ 4.36, m, 1H; δ 3.77, s, 3H; δ 3.29, m,1H; δ 3.20, m, 2H; δ 3.07, m, 1H; δ 1.98, m, 1H; δ 1.84, m, 4H; δ 1.59,m, 1H), LC/MS (APCI, ES, M+H=389).

Example 110

2-[(Aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamidetrifluoroacetate To a stirred solution oftert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylatedissolved in a small amount of methanol was added 4.0 N HCl in dioxane.The solution was stirred for 1 h at RT. The product was purified byGilson (5% MeCN—H₂O→98MeCN—H₂O) to yield 27 mg of the title compound asthe trifluoroacetate salt. ¹H NMR (300 MHz, d₃-MeOD; δ 7.55(d, 2H),7.45(s, 1H), 7.05(d, 2H), 4.35(dd, 2H), 4.25(m, 1H), 3.60(dd, 2H),3.50(m, 1H), 3.30(m, 5H), 2.95(dd, 2H), 2.10(dd, 2H), 1.80(m, 2H),1.35(t, 6H)), LCMS, (ES, M+H=460).

Example 112tert-Butyl(3S)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylatetrifluoroacetate

Methyl{4-[2-(diethylamino)ethoxy]phenyl}acetate To a solution ofmethyl(4-hydroxyphenyl)acetate (16.6 g, 10 mmol) in DMF (100 mL) wasadded 2-bromo-N,N-diethylethanamine hydrobromide (2.6 g, 10 mmol) and),Cs₂CO₃ (6.6 g, 20 mmol). After 1 h an additional equivalent of thebromide was added and then stirred overnight at room temperature. Thereaction mixture was poured in to a large volume of cold water. Theproduct was then isolated by filtration and purified by columnchromatography (SiO₂, 10% MeOH/DCM) to give 15.6 g of the title compoundas an off-white solid. LC/MS (APCI, ES, M+H=266).

{4-[2-(Diethylamino)ethoxy]phenyl}acetaldehyde To a stirred solution ofmethyl {4-[2-(diethylamino)ethoxy]phenyl}acetate (5.3 g, 20 mmol) inanhydrous toluene (100 L) cooled to −78° C. under N₂ was addeddiisobutylaluminum hydride (DIBAL, 1.0M in toluene, 100 mL, 100 mmol)over a period of 10-15 minutes. The mixture was stirred at −78° C. foran additional 2 h. The reaction was quenched by the slow addition ofMeOH, followed by the introduction of 10% Rochelle's Salt. Thesuspension was diluted with EtOAc and stirred at room temperature for 1h. The EtOAc layer was set aside and the aqueous layer was extractedwith EtOAc(2×). The combined organic layers were combined and dried overNa₂SO₄ and filtered. The solution was concentrated under vacuum to yield4.7 g (100%) of the title aldehyde as a yellow viscous semisolid, whichwas used in the next step without purification. LC/MS (APCI, ES,M+H=236).

Methyl2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxylate To asolution of {4-[2-(diethylamino)ethoxy]phenyl}acetaldehyde (4.7 g, 20mmol) in DMF (30 mL) was added cyanomethyl acetate (1.5 nL, 20 mmol) andsulfur (0.6 g, 20 mmol), followed by diisopropylethylamine (Hunig'sBase, 2.5 mL, 20 mmol). The resultant suspension immediately turned darkyellow to brown with an exotherm. The reaction mixture was stirredovernight at room temperature. The reaction was slowly added to water(˜200 mL) while stirring. A tan precipitate formed and was filteredafter an additional 30 minutes of stirring. The resultant solid waspurified by column chromatography (SiO₂, 5-10% MeOH/DCM/0.5% NH₄OH) toyield 2.4 g of the title compound as a light yellow solid. LC/MS (APCI,ES, M+H=349).

2-Amino-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxylic acidTo a stirred solution of methyl2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxylate (2.0g, 5.7 mmol) in MeOH (50 mL) was added 6N NaOH (50 mL) and water (50mL). The reaction was heated to reflux for 2 h or until startingmaterial was gone by TLC or LCMS. The solution was concentrated undervacuum to about half of the original volume. The pH of the resultantcloudy mixture was adjusted to 3-5 by the careful addition of 6N HCl(˜150 mL) while stirring. The gummy red precipitate was filtered anddried. Purification was achieved by triturating in boiling hexanes. Theproduct (1.6 g) was isolated in pure form by filtration after cooling toroom temperature and drying in a vacuum oven overnight. LC/MS (APCI, ES,M+H=335).

tert-Butyl(3S)-3-{[(2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylateTo a stirred solution of2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxylic acid(100 mg, 0.3 mmol) in anhydrous DMF (2.0 mL) is added(S)-3-amino-azepane-1-carboxylic acid tert-butyl ester (60 mg, 0.3mmol), EDCI (63 mg, 0.33 mmol), HOBt (61 mg, 0.45 mmol), and NMM (0.04mL, 0.3 mmol). The reaction mixture was stirred overnight at roomtemperature. The solution was diluted with water and EtOAc. The organiclayer was separated and set aside. The remaining aqueous layer wasextracted with EtOAc (2×) and then the combined organic extracts werepooled and washed with brine. The resultant EtOAc solution was driedover Na₂SO₄, filtered, and concentrated under vacuum to yield a brownsolid. Purification was performed by Gilson (5% MeCN—H₂O→98% MeCN—H₂O)to give 90 mg of an off-white solid. LC/MS (APCI, ES, M+H=517).

tert-Butyl(3S)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylateTo a stirred solution oftert-butyl(3S)-3-{[(2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate(90 mg, 0.17 mmol) in anhydrous THF (5.0 mL) was added trichloroacetylisocyanate (0.09 mL, 0.7 mmol) slowly over a period of 5 min. After theaddition was complete, a precipitate formed and the reaction stirred foran additional 1 h. The reaction mixture was concentrated in a vacuum.The crude residue was dissolved in methanol and then charged with 2.0NNH₃ in methanol (0.35 mL). Purification by Gilson (5% MeCN—H₂O→98%MeCN—H₂O) gave the title (50 mg) as a tan solid. ¹H NMR (300 MHz,d₃-MeOD; δ 7.55(d, 2H), 7.45(s, 1H), 7.05(d, 2H), 4.35(dd, 2H),3.60-3.90(m, 3H), 3.60(dd, 2H), 3.30(m, 4H), 2.95(m, 2H), 1.90(dd, 2H),1.55(m, 2H), 1.45(s, 9H), 1.35(t, 6H)), (APCI, ES, M+H=560).

Example 123N-[(3S)-Azepan-3-yl]-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamidehydrochloride

2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid. To a stirredsolution of 2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acidmethyl ester (6.6 g, 26.6 mmol) in MeOH (200 mL) was added 6N NaOH (100mL) and water (50 mL). The reaction was heated to reflux for 2 h oruntil starting material was gone by TLC or LCMS. The solution wasconcentrated under vacuum to about half of the original volume. The pHof the resultant cloudy mixture was adjusted to 3-5 by the carefuladdition of 6N HCl (˜150 mL) while stirring. The gummy red precipitatewas filtered and dried. Purification was achieved by triturating inboiling hexanes. The product (6.0 g, 91%) was isolated in pure form byfiltration after cooling to room temperature and drying in a vacuum ovenovernight. ¹H NMR (d₆-DMSO δ 7.37, d, 2H, δ 7.11, s, 1H; δ 7.10, br s,2H; δ 6.94, d, 2H), LC/MS (APCI, ES, M+H=250).

Pyrazine-2-carboxylic acid hydrazide. To a stirred solution ofpyrazine-2-carboxylic acid methyl ester (11.1 g, 80 mmol) in 140 mL ofEtOH was added hydrazine hydrate (15.6 mL, 320 mmol). The resultantsolution was heated to reflux for 2 h. The solvent was removed underreduced pressure and dried under high vacuum to yield the title amide(11.1 g, 100%) as a white solid. The product was used in subsequentsteps without purification. ¹H NMR (d₆-DMSO δ 10.1, br s, 1H; δ 9.12, d,1H; δ 8.83, d, 1H; δ 8.70, dd, 1H; δ 4.64, br s, 2H), LC/MS (APCI, ES,M+H=139).

Pyrazine-2-carbonyl azide. Pyrazine-2-carboxylic acid hydrazide (11.1 g,80 mmol) was dissolved in 140 mL of water and charged with 6N HCl (13.3mL, 80 mmol) and cooled to 0° C. To the stirred reaction mixture wasadded a solution of sodium nitrite (8.3 g, 120 mmol) in 80 mL of waterwas added slowly over a period of 15-30 minutes using an additionfunnel. After the addition was complete the reaction was warmed to roomtemperature and stirred for an additional 5 h. The solution was theneutralized by the careful addition of solid NaHCO₃ and then extractedwith CHCl₃ (3×). The pooled organic fractions were dried over Na₂SO₄,filtered, concentrated and dried under high vacuum overnight to yield2.5 g (21%) the title acyl azide. The product was used in subsequentsteps without purification. ¹H NMR (d₆-DMSO δ 9.30, d, 1H; δ 9.03, d,1H; δ 8.90, dd, 1H).

(S)-3-{[2-Amino-5-(4-methoxy-phenyl)-thiophene-3-carbonyl]-amino}-azepane-1carboxylicacid tert-butyl ester. To a stirred solution of2-amino-5-(4-methoxy-phenyl)-thiophene-3-carboxylic acid (1.0 g, 4.0mmol) in anhydrous DMF (20 mL) is added (S)-3-amino-azepane-1-carboxylicacid tert-butyl ester (1.03 g, 4.8 mmol), BOP (2.6 g, 6.0 mmol) and NMM(0.6 mL, 5 mmol). The reaction mixture was stirred overnight at roomtemperature. The solution was diluted with water and EtOAc. The organiclayer was separated and set aside. The remaining aqueous layer wasextracted with EtOAc (2×) and then the combined organic extracts werepooled and washed with brine. The resultant EtOAc solution was driedover Na₂SO₄, filtered, and concentrated under vacuum to yield a brownsolid. Purification was performed by ISCO MPLC (SiO₂, 30-50%EtOAc/hexanes) to give 0.9 g (50%) of an off-white solid. ¹H NMR(d₆-DMSO δ 7.51, d, 0.5H; δ 7.46, s, 0.5H; δ 7.37, s, 0.5H; δ 7.36, d,0.5H; δ 7.34, br s, 2H; δ 7.33, d, 2H; δ 6.93, d, 2H; δ 4.11, br s, 1H;δ 3.76, s, 3H; δ 3.61, dq, 1H; δ 3.47, m, 1H; δ 3.11, m, 2H; δ 1.73, m,3H; δ 1.56, m, 2H; δ 1.42, s, 4.5H; δ 1.38, s+m, 5.5H;), LC/MS (APCI,ES, M+H=446).

tert-Butyl(3S)-3-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}azepane-1-carboxylate.A solution of(S)-3-{[2-amino-5-(4-methoxy-phenyl)-thiophene-3-carbonyl]-amino}-azepane-1carboxylicacid tert-butyl ester (0.76 g, 1.7 mmol) and pyrazine-2-carbonyl azide(0.5 g, 3.4 mmol) in 20 mL of anhydrous DME was refluxed for 2 h. Thesolvent was removed under reduced pressure and the crude product waspurified using ISCO MPLC (40-60% EtOAc/hexanes) to give the title 0.51 g(53%) compound as a light yellow solid. ¹H NMR (d₆-DMSO δ 12.5, br s,0.5H; δ 12.4, br s, 0.5H; δ 10.90, s, 0.5H; δ 10.88, s, 0.5H; δ 8.93, s,0.5H; δ 8.89, s, 0.5H; δ 8.33, d, 1H; δ 8.29, t, 1H; δ 8.05, d, 0.5H; δ7.91, d, 0.5H; δ 7.74, s, 0.5H; δ 7.65, s, 0.5H; δ 7.52, dd, 2H; δ 7.00,d, 2H; δ 4.26, m, 0.5H; δ 4.17, m, 0.5H; δ 3.79, s, 3H; δ 3.69, m, 1H; δ3.48, m, 1H; δ 3.21, m, 2H; δ 1.77, m, 3H; δ 1.61, m, 2H; δ 1.44, s,4.5H; δ 1.38, s+m, 5.5H), LC/MS (APCI, ES, M+H=567).

N-[(3S)-Azepan-3-yl]-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;hydrochloride. To a stirred solution oftert-butyl(3S)-3-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}azepane-1-carboxylate(0.51 g, 0.9 mmol) in 10 mL of MeOH is added 10 mL (40 mmol) of 4.0 NHCl in dioxane. The solution was stirred at room temperature for 4 h andthen concentrated under vacuum. The residue was partially recrystallizedby triturating in refluxing 2-propanol to yield the title compound are alight orange solid (0.30 g, 67%). ¹H NMR (d₆-DMSO δ 12.6, br s, 1H; δ10.9, s, 1H; δ 9.55, br s, 1H; δ 9.24, br s, 1H; δ 8.88, s, 1H; δ 8.49,d, 1H; δ 8.35, dd, 1H; δ 8.29, d, 1H; δ 7.92, s, 1H; δ 7.54, d, 2H; δ6.99, d, 2H; δ 4.42, m, 1H; δ 3.33, m, 1H; δ 3.23, m, 2H; δ 3.10, m, 1H;δ 2.02, m, 1H; δ 1.85, m, 4H; δ 1.62, m, 1H;), LC/MS (APCI, ES,M+H=467).

Example 1362-[(Aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamidetrifluoroacetate

tert-Butyl(3S)-3-{[(5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(hydroxyamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate To asolution of tert-butyl(3S)-3-{[(2-amino-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate(115 mg, 0.22 mmol) in THF (640 μL) was added 1,1′-carbonyl diimidazole(178 mg, 1.1 mmol). The resulting cloudy solution was stirred at rt for1 h whereupon hydroxylamine hydrochloride (76.4 mg, 1.1 mmol) and Et₃N(100 μL) were added and the resulting dark solution was stirred for 48 hat rt. The mixture was partitioned between EtOAc and H₂O and the organiclayer was washed with H₂O, brine and dried (MgSO₄). Evaporation affordeda yellow residue. Purification by Gilson (5% MeCN—H₂O→98% MeCN—H₂O) gavethe title hydroxy urea.

5-{4-[2-(Diethylamino)ethoxy]phenyl}-2-{[(hydroxyamino)carbonyl]amino}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamideA stirred solution oftert-butyl(3S)-3-{[(5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(hydroxyamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylatein dioxane was treated with 4.0N HCl solution in dioxane (3 mL) and theresulting cloudy mixture was stirred at rt for 1 h. Evaporation of thesolvent gave5-[4-(2-diethylamino-ethoxy)-phenyl]-2-(3-hydroxy-urea)-thiophene-3-carboxylicacid-(S)-piperidin-3-ylamide as the hydrochloride salt (8 mg). ¹H NMR(300 MHz, DMSO-d₆) δ ppm 1.17-1.40 (m, 6H) 1.54-1.81 (m, 2H) 1.84-2.07(m, 2H) 2.76-2.99 (m, 2H) 3.05-3.25 (m, 4H) 3.41-3.61 (m, 4H) 3.73-3.88(m, 1H) 4.29-4.42 (m, 1H) 4.40-4.64 (m, 1H) 5.86 (s, 1H) 7.07 (d, J=8.48Hz, 2H) 7.55 (d, J=8.48 Hz, 2H) 7.82 (s, 1H) 9.44 (s, 1H) 9.65 (s, 1H);LC/MS (ES, M+H=476).

Example 1372-[(Aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3-carboxamidetert-Butyl(3S)-3-[({2-[(aminocarbonyl)amino]-5-bromo-3-thienyl}carbonyl)amino]azepane-1-carboxylate

To a solution of methyl2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxylate (1 equiv) in dryTHF (0.3 M) was added a solution of[Me₂Al—Boc-3-(S)-aminohomopiperidine] (2 equiv) in THF (1.0 M) (whichwas preformed by the addition of Me₃Al (2.0 M in hexanes) to a solutionof Boc-3-(S)-homopiperidine in THF at −78° C. and the resulting yellowsolution was warmed to room temperature and stirred for an additional 15min) and the resulting deep yellow solution was stirred overnight atroom temperature. The reaction mixture was cooled with ice and a 10%aqueous solution of Rochelle's salt was added slowly to quench thereaction. The resulting biphasic solution was warmed to room temperatureand stirred for an additional 1 h. The mixture was diluted with EtOAcand H₂O, the aqueous layer was extracted with EtOAc (3×) and thecombined organic extracts were washed with H₂O, brine and dried (MgSO₄).Evaporation gave a pale orange solid. Purification by columnchromatography (40-60% EtOAc/Hexanes) gave a white solid. LC/MS (ES,M+H=462).

tert-Butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)azepane-1-carboxylateA flask was loaded withtert-butyl(3S)-3-[({2-[(aminocarbonyl)amino]-5-bromo-3-thienyl}carbonyl)amino]azepane-1-carboxylate(1.0 mmol), 3-methoxyphenylboronic acid (1.5 mmol), Cs₂CO₃ (3.0 mmol)and Pd(PPh₃)₄ (0.05-0.1 mmol) and was purged with nitrogen for 10 mins.Dioxane (4 mL) and H₂O (1 mL) were added under nitrogen atmosphere andthe resulting mixture was heated to 90° C. for 2-4 h. The mixture wasallowed to cool to RT and the mixture was filtered (0.45 uM ordiatomaceous earth). The water layer was separated and remaining solventwas concentrated to dryness. The residue was purified by columnchromatography (SiO₂) on an MPLC ISCO separation system (30-60%EtOAc/hexanes) to give an off-white solid. LCMS, (ES, M+H=489).

2-[(Aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3-carboxamidehydrochloride To a stirred solution oftert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)azepane-1-carboxylatedissolved in a small amount of methanol was added 4.0 N HCl in dioxane.The solution was stirred for 1 h at RT. The product as the hydrochloridesalt was obtained as an off-white solid after removal of the solvent anddrying. ¹H NMR (d₆-DMSO δ 10.90 (s, 1H), 9.21 (s, 1H), 9.01 (s, 1H),8.29 (d, 1H), 7.93 (s, 1H), 7.29 (t, 1H), 7.11 (d, 2H), 7.03 (s, 1H),6.83 (d, 1H), 4.33 (s, 1H), 3.81 (s, 3H), 3.20 (m, 4H), 2.00 (m, 1H),1.84 (m, 4H), 1.56 (m, 1H)), LCMS, (ES, M+H=389).

Example 1392-[(Aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide

Methyl2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate. To astirred solution of 2-amino-thiophene-3-carboxylic acid methyl ester (1eq) in anhydrous THF (mL) was added trichloroacetyl isocyanate (1 eq)slowly over a period of 5 min. After the addition was complete, aprecipitate formed and the reaction stirred for an additional 1 h. Thedesired product was obtained by filtration to give methyl2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (99%)as an off-white solid. The product was used in the next step without anyfurther purification. LC/MS (ES, M+H=345).

Methyl5-bromo-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate.To a stirred solution of methyl2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate (1eq) in glacial acetic acid (20 mL) was added a solution of bromine (1.3eq) in glacial acetic acid (5 mL) slowly over a period of 5 min. Afterthe addition was complete, the resulting dark solution was stirred for30 mins at RT. The solvent was evaporated under vaccum and the residuewas triturated with H₂O. The title compound was obtained by filtration(99%) as an off-white solid. The product was used in the next stepwithout any further purification after drying for 2 days under P₂O₅.LC/MS (ES, M+H=425).

Methyl 2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxylate. Astirred solution of methyl5-bromo-2-({[(trichloroacetyl)amino]carbonyl}amino)thiophene-3-carboxylate(1 eq) in anhydrous methanol was purged with dry ammonia for 20 mins.After stirring for extra 10 mins at RT, precipitation was observed andthe product was isolated by filtration (100% yield). LC/MS (ES,M+H=280).

tert-Butyl(3S)-3-[({2-[(aminocarbonyl)amino]-5-bromo-3-thienyl}carbonyl)amino]piperidine-1-carboxylate

To a solution of methyl2-[(aminocarbonyl)amino]-5-bromothiophene-3-carboxylate (1 equiv) in dryTHF (0.3 M) was added a solution of [Me₂Al—Boc-3-(S)-aminopiperidine] (2equiv) in THF (1.0M) (which was preformed by the addition of Me₃Al (2.0Min hexanes) to a solution of Boc-3-(S)-piperidine in THF at −78° C. andthe resulting yellow solution was warmed to room temperature and stirredfor an additional 15 min) and the resulting deep yellow solution wasstirred overnight at room temperature. The reaction mixture was cooledwith ice and a 10% aqueous solution of Rochelle's salt was added slowlyto quench the reaction. The resulting biphasic solution was warmed toroom temperature and stirred for an additional 1 h. The mixture wasdiluted with EtOAc and H₂O, the aqueous layer was extracted with EtOAc(3×) and the combined organic extracts were washed with H₂O, brine anddried (MgSO₄). Evaporation gave a pale orange solid. Purification bycolumn chromatography (40-60% EtOAc/Hexanes) gave a white solid. ¹H NMR(d₆-DMSO, δ 10.9, s, 1H; δ 9.48, br s, 1H; δ 9.31, br s, 1H; δ 8.48, d,1H; δ 8.10, s, 1H, δ 7.57, d, 2H, δ 7.38, t, 2H, δ 7.23, t, 1H, δ 7.01,br s, 2H; δ 4.26, m, 1H; δ 3.29, m, 1H, δ 3.11, m, 1H, δ 2.94, m, 2H; δ1.91, m, 2H; δ 1.69, m, 2H), LC/MS (APCI, ES, M+H=345).

tert-Butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylateA flask was loaded withtert-butyl(3S)-3-[({2-[(aminocarbonyl)amino]-5-bromo-3-thienyl}carbonyl)amino]piperidine-1-carboxylate(1.0 mmol), 3-methoxyphenylboronic acid (1.5 mmol), Cs₂CO₃ (3.0 mmol)and Pd(PPh₃)₄ (0.05-0.1 mmol) and was purged with nitrogen for 10 mins.Dioxane (4 mL) and H₂O (1 mL) were added under nitrogen atmosphere andthe resulting mixture was heated to 90° C. for 2-4 h. The mixture wasallowed to cool to RT and the mixture was filtered (0.45 uM ordiatomaceous earth). The water layer was separated and remaining solventwas concentrated to dryness. The residue was purified by columnchromatography (SiO₂) on an MPLC ISCO separation system (30-60%EtOAc/hexanes) to give an off-white solid. LCMS, (ES, M+H=475).

2-[(Aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamidehydrochloride To a stirred solution oftert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylatedissolved in a small amount of methanol was added 4.0 N HCl in dioxane.The solution was stirred for 1 h at RT. The product as the hydrochloridesalt was obtained as an off-white solid after removal of the solvent anddrying. ¹H NMR (d₆-DMSO δ 10.94 (s, 1H), 9.41 (s, 1H), 9.19 (s, 1H),8.47 (d, 1H), 8.11 (s, 1H), 7.30 (t, 1H), 7.15 (d, 1H), 7.05 (br, 2H),6.84 (d, 1H), 4.25 (s, 1H), 3.82 (s, 3H), 3.29 (d, 1H), 3.12 (d, 1H),2.97 (m, 2H), 1.92 (d, 2H), 1.69 (m, 2H)), LCMS, (ES, M+H=375).

Other Examples

Examples 1-3, 5-25, and 27-109 were prepared in a similar fashion tothat described for examples 4 and 26.

Examples 111 and 113-115 were prepared in a similar fashion to thatdescribed for examples 110 and 112.

Examples 116-119 were prepared according to the general Scheme V.

Examples 121-122 and 124-135 were prepared in a similar fashion to thatdescribed for examples 123 and 136.

Examples 138 and 140 were prepared in a similar fashion to thatdescribed for examples 137 and 139.

1. A compound of formula (I) or a pharmaceutically acceptable salt or invivo-hydrolysable precursors thereof:

wherein: R¹ and R² are at each occurrence independently selected from H,optionally substituted C₁₋₆alkyl, or optionally substitutedheterocyclyl; with the proviso that R¹ and R² are not both H; or R¹ andR² and the N to which they are attached in combination form anoptionally substituted heterocyclyl; R⁴ is selected from H, OH,optionally substituted carbocyclyl, optionally substituted heterocyclyl,or optionally substituted C₁₋₆alkyl; R⁵ is selected from H, optionallysubstituted carbocyclyl, or optionally substituted C₁₋₆alkyl.
 2. Acompound of formula (I) or a pharmaceutically salt or an invivo-hydrolysable precursor thereof as recited in claim 1 wherein R²,R⁴, and R⁵ have any of the meanings defined in claim 1 and R¹ is anoptionally substituted heterocyclyl.
 3. A compound of formula (I) or apharmaceutically salt or an in vivo-hydrolysable precursor thereof asrecited in claim 1 wherein R², R⁴, and R⁵ have any of the meaningsdefined in claim 1 and R¹ is an optionally substituted heterocyclylwherein 1, 2, or 3 substitutents is/are independently selected fromhalogen, nitro, amino, cyano, trifluoromethyl, alkyl, alkenyl, alkynyl,haloalkyl, alkoxy, hydroxy, alkylhydroxy, carbonyl, —CH(OH)CH₃,—CH₂NH-alkyl-OH, alkyl-(OH)CH₃, —CH₂-phenyl-(OCH₃)₂, —Oalkyl, —OCH₃,—Ophenyl, —OCOalkyl, —NHCHO, —Nalkyl, —N-(alkyl)-CHO, —NH—CO-amino,—N-(alkyl)-CO-amino, —NH—COalkyl, —N-(alkyl)-COalkyl, -carboxy,-amidino, —CO-amino, —CO-alkyl, —CO₂alkyl, mercapto, —Salkyl,—SCH₂furanyl, —SO(alkyl), —SO₂(alkyl), —SO₂-amino, -alkylsulfonylamino,phenyl, anisole, dimethoxyphenyl, trimethoxyphenyl, halophenyl,cycloalkyl, heterocyclyl, -alkyl-NH-cycloalkyl, -alkyl-NH— heterocyclyl,-alkyl-NH-alkyl-OH, —C(═O)OC(CH₃)₃, —N(CH₃)₂, —N(CH₂CH₃)₂,-alkyl-NH-alkyl-heterocyclyl, -alkyl-aryl, -methyl-phenyl,alkyl-polycyclyl, alkyl-amino, alkyl-hydroxy, —CH₂NH-alkyl-heterocyclyl,—CH₂NHCH2CH(CH₃)₂, vicinal —O(alkyl)O—, vicinal —OC(haloalkyl)O—,vicinal —CH₂O(alkyl)O—, vicinal —S(alkyl)S— and —O(alkyl)S—.
 4. Acompound of formula (I) or a pharmaceutically salt or an invivo-hydrolysable precursor thereof as recited in claim 1 wherein R²,R⁴, and R⁵ have any of the meanings defined in claim 1 and R¹ is anoptionally substituted heterocyclyl wherein 1, 2, or 3 substituentsis/are independently selected from: —OH, C(═O)OC(CH₃)₃, NH₂, C₁₋₆-alkyl,methoxybenzene, or dimethoxy benezene.
 5. A compound of formula (I) or apharmaceutically salt or an in vivo-hydrolysable precursor thereof asrecited in claim 1 wherein R², R⁴, and R⁵ have any of the meaningsdefined in claim 1 and R¹ is a heterocyclyl wherein heterocyclyl isselected from piperdinyl, pyridinyl, pyrrolidinyl, pyrazinyl, azepanyl,azetidinyl, azabicyclozinyl, furanyl, thienyl.
 6. A compound of formula(I) or a pharmaceutically salt or an in vivo-hydrolysable precursorthereof as recited in claim 1 wherein R¹, R⁴, and R⁵ have any of themeanings defined in claim 1 and R² is H.
 7. A compound of formula (I) ora pharmaceutically salt or an in vivo-hydrolysable precursor thereof asrecited in claim 1 wherein R¹, R², and R⁵ have any of the meaningsdefined in claim 1 and R⁴ is H.
 8. A compound of formula (I) or apharmaceutically salt or an in vivo-hydrolysable precursor thereof asrecited in claim 1 wherein R¹, R², and R⁴ have any of the meaningsdefined in claim 1 and R⁵ is H or an optionally substituted C₁₋₆alkyl.9. A compound of formula (I) or a pharmaceutically salt or an invivo-hydrolysable precursor thereof as recited in claim 1 wherein R¹,R², and R⁴ have any of the meanings defined in claim 1 and R⁵ is H or anoptionally substituted C₁₋₆alkyl wherein 1, 2 or 3 substituents is/areindependently selected from: NH₂, NHCH₃, N(CH₂CH₃)₂, N(CH₃)₂, OCH3, OH,—C₁₋₆alkyl, morpholino, piperidinyl, pyrrolodinyl.
 10. A compound offormula (I) or a pharmaceutically salt or an in vivo-hydrolysableprecursor thereof as recited in claim 1 wherein R¹, R², and R⁴ have anyof the meanings defined in claim 1 and R⁵ is H or an optionallysubstituted C₁₋₃alkyl.
 11. A compound of formula (I) or apharmaceutically salt or an in vivo-hydrolysable precursor thereof asrecited in claim 1 wherein R¹, R², and R⁴ have any of the meaningsdefined in claim 1 and R⁵ is H or an optionally substituted C₁₋₃alkylwherein 1, 2 or 3 substituents is/are independently selected from: NH₂,NHCH₃, N(CH₂CH₃)₂, N(CH₃)₂, OCH3, OH, —C₁₋₆alkyl, morpholino,piperidinyl, pyrrolodinyl.
 12. A compound of formula (I) or apharmaceutically salt or an in vivo-hydrolysable precursor thereof, asrecited in claim 1 wherein: R¹ is an optionally substitutedheterocyclyl; R² is H; R⁴ is H; R⁵ is H or an optionally substitutedC₁₋₆alkyl.
 13. A compound of formula (I) or a pharmaceutically salt oran in vivo-hydrolysable precursor thereof, as recited in claim 1wherein: R¹ is an optionally substituted heterocyclyl wherein thesubstituent is selected from one or more of the following: —NH₂,C₁₋₆alkyl, —C(═O)OC(CH₃)₃, R² is H; R⁴ is H; R⁵ is H or an optionallysubstituted C₁₋₆alkyl wherein the substituent is selected from one ormore of the following: —C₁₋₆alkyl, —N(C₁₋₃alkyl)₂.
 14. A compound offormula (I) or a pharmaceutically salt or an in vivo-hydrolysableprecursor thereof, as recited in claim 1 wherein: R¹ is an optionallysubstituted heterocyclyl wherein the substituent is selected from one ormore of the following: —NH₂, C₁₋₆alkyl, —C(═O)OC(CH₃)₃, R² is H; R⁴ isH; R⁵ is H or an optionally substituted C₁₋₃alkyl wherein 1, 2 or 3substituent is/are independently selected from: NH₂, NHCH₃, N(CH₂CH₃)₂,N(CH₃)₂, OCH3, OH, —C₁₋₆alkyl, morpholino, piperidinyl, pyrrolodinyl.15. A compound of formula (I) or a pharmaceutically salt or an invivo-hydrolysable precursor thereof, as recited in claim 1 wherein: R¹is a heterocyclyl; R² is H; R⁴ is H; R⁵ is H or a C₁₋₆alkyl.
 16. Acompound of formula (I) or a pharmaceutically salt or an invivo-hydrolysable precursor thereof, as recited in claim 1 wherein: R¹is a 6-membered heterocyclyl containing at least one N in the ring; R²is H; R⁴ is H; R⁵ is a C₁₋₃alkyl.
 17. A compound of formula (I) selectedfrom: tert-butyl3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;tert-butyl3-{[(2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[(3R)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{4-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxymethyl)phenyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(2-aminoethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1-methylpiperidin-4-yl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylazepan-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxymethyl)phenyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylpiperidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[2-(dimethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[2-(diethylamino)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(piperidin-4-ylmethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyrrolidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(1-ethylpiperidin-3-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[(3S)-1-ethylazepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(3-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)pyrrolidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-piperidin-3-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(1-benzylpiperidin-4-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;tert-butyl3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-azetidin-3-yl-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(2S)-pyrrolidin-2-ylmethyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyridin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperidin-1-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-1-azabicyclo[2.2.2]oct-3-yl-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(2-hydroxyethyl)-5-(4-hydroxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(trans-4-hydroxycyclohexyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(2-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(tetrahydrofuran-2-ylmethyl)thiophene-3-carboxamide;tert-butyl(3R)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-3-ylmethyl)thiophene-3-carboxamide;tert-butyl3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azetidine-1-carboxylate;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-4-ylmethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(3-methoxypropyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide;N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]urea;2-[(aminocarbonyl)amino]-N-(2-methoxyethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-{2-[(2-furylmethyl)thio]ethyl}-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide;N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{3-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinolin-3-yl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(1,3-benzodioxol-5-ylmethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(3-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-[2-(3,4-dimethoxyphenyl)ethyl]-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(5-methyl-2-furyl)methyl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-N-(4-fluorobenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;tert-butyl4-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-N-(2-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-phenoxyethyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-2-ylethyl)thiophene-3-carboxamide;tert-butyl4-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-N-(4-methoxybenzyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide;tert-butyl(3S)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxamide;tert-butyl(3R)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;N-[3-{[(3S)-3-aminoazepan-1-yl]carbonyl}-5-(4-methoxyphenyl)-2-thienyl]urea;5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;N-(2-aminoethyl)-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;5-(4-methoxyphenyl)-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;tert-butyl3-{[(5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide;5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide;N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea;N-[3-[(3-aminopyrrolidin-1-yl)carbonyl]-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea;tert-butyl4-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;tert-butyl3-{[(5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate;5-[4-(2-diethylamino-ethoxy)-phenyl]-2-(3-hydroxy-urea)-thiophene-3-carboxylicacid-(S)-piperidin-3-ylamide;2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(2-hydroxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide;2-[(aminocarbonyl)amino]-5-[2-(benzyloxy)phenyl]-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide.18. (canceled)
 19. (canceled)
 20. A method for the treatment of cancercomprising administering to a human a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof as defined in claim
 1. 21. A method for the treatment of breastcancer, colorectal cancer, ovarian cancer, lung (non small cell) cancer,malignant brain tumors, sarcomas, melanoma and lymphoma by administeringa compound of formula I or a pharmaceutically acceptable salt thereof asdefined in claim
 1. 22. A method of treating cancer by administering toa human a compound of formula (I) or a pharmaceutically acceptable saltthereof as defined in claim 1 and an anti-tumor agent.
 23. A method oftreating cancer by administering to a human a compound of formula (I) ora pharmaceutically acceptable salt thereof as defined in claim 1 and aDNA damaging agent.
 24. A method for the treatment of infectionsassociated with cancer comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof as defined inclaim
 1. 25. A method for the prophylaxis treatment of infectionsassociated with cancer comprising administering to a host in need ofsuch treatment a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof as defined inclaim
 1. 26. A pharmaceutical composition comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof as defined inclaim 1 together with at least one pharmaceutically acceptable carrier,diluent or excipient.
 27. A process for the preparation of a compound offormula (I) or a pharmaceutically acceptable salt or invivo-hydrolysable precursors thereof as defined in claim 1, whichcomprises: (a) the reaction of a 2-aminothiophene shown below as FormulaII

wherein the hydrogen at the 2-amino position is displaced to form anamide, shown as formula III below

wherein the methyl ester is converted to an amide utilizing the desiredamine in conjuntion conjunction with an aluminate organometalliccomplex, to give the product shown as formula IV below:

Wherein the amide is converted to various substituted secondary ureas bythe reaction with various isocyanantes to yield the product shown asformula V below:


28. (canceled)